Celiac disease and risk of neuropsychiatric disorders: A nationwide cohort study.

INTRODUCTION: Previous studies have indicated that patients with celiac disease (CD) may have an increased risk of developing neuropsychiatric disorders. However, large-scale epidemiologic studies on the topic are still scarce. We aimed to examine the association between CD and development of neuropsychiatric disorders during an 18-year follow-up period. METHODS: We conducted a prospective cohort study. All Danish patients with an incident diagnosis of CD (ICD-10 K90.0) from 2000 to 2018 were identified in nationwide registries and compared with birthdate- and sex-matched controls (variable 1:10 ratio) for the development of a neuropsychiatric disease. Individual neuropsychiatric diseases were also examined. The absolute risk was calculated by the cumulative incidence, and the relative risk was estimated in Cox regression models. RESULTS: We identified a cohort of 6329 patients with CD diagnosed from 2000 to 2018 and 63,287 matches at risk for developing incident neuropsychiatric disorders. The cumulative incidence of development of any neuropsychiatric disorder was 3.9%, 14.9%, 24.8%, 35.9% after 1, 5, 10, and 15 years of follow-up, respectively, in patients with CD compared with 1.8%, 9.3%, 18.3%, and 27.0% in controls. Gray's test for equality p < 0.001. The relative risk was HR = 1.58 (95% confidence interval: 1.49-1.68) in CD patients compared with matches. For the individual outcomes, CD was associated with an increased relative risk of developing anxiety, depression, eating disorders, epilepsy, migraine, and stress. We also found indications of an increased relative risk of ADHD, alcoholism, bipolar disorders, and drug abuse, although the associations were less clear. No associations were found between CD and dementia, Parkinson's disease, and schizophrenia. CONCLUSIONS: In this nationwide study including more than 6000 patients with CD, we found an increased risk of development of a neuropsychiatric disorder compared with age- and sex-matched controls. The causes and the clinical relevance of these associations remain to be elucidated.

Newly Diagnosed Celiac Disease and Bone Health in Young Adults: A Systematic Literature Review.

Celiac disease (CD), a gluten-induced autoimmune disease, is associated with low bone mineral density (BMD) among children. Unfortunately, it is often diagnosed in adulthood, which may lead to an increased risk of fragile bones. The aim of this systematic review was to report on BMD status among young adults newly diagnosed with CD, and to examine the effect of a gluten-free diet (GFD), nutritional supplements, such as vitamin D, or antiresorptive medications on BMD recovery. Databases searched were Medline, Embase, and Cochrane Library up to July 2nd, 2020. Both observational studies and clinical trials were considered, if patients were newly diagnosed and between 20 and 35 years of age and reported on BMD. We critically appraised the identified studies using ROBINS-I and summarized the findings narratively. Out of 3991 references, we identified 3 eligible studies: one cross-sectional study and two longitudinal studies. In total, 188 patients were included, and the study population consisted primarily of women with an age range between 29 and 37 years old. Compared to healthy controls, our target population had lower BMD. Moreover, a strict GFD may increase BMD during a follow-up period of up to 5 years. Newly diagnosed CD patients aged 20-35 years are at risk of lower BMD. Therefore, it may be crucial to assess BMD at time of diagnosis in young women. Whether the results can be extrapolated to young men is unknown. While strict GFD may improve BMD over time, there is a lack of robust evidence to demonstrate that nutritional supplements or antiresorptive agents are beneficial in the prevention of fragile bones in this age group.

Symptoms and biomarkers associated with undiagnosed celiac seropositivity.

BACKGROUND: Studies have indicated that underdiagnosis and diagnostic delay are common in celiac disease. Therefore, it is important to increase our knowledge of what symptoms and biomarkers could identify undiagnosed cases of celiac disease. METHODS: We screened for celiac disease antibodies in stored blood samples from 16,776 participants in eight population-based studies examined during 1976-2012. Undiagnosed celiac seropositivity was defined as celiac disease antibody positivity (IgG-deamidated gliadin peptide above 10.0 U/mL and/or IgA-tissue transglutaminase (TTG) or IgG-TTG above 7.0 U/mL) without a known diagnosis of celiac disease in the National Patient Register. In all studies general health symptoms were recorded by participant-completed questionnaire, including self-perceived health, tiredness, headache and gastrointestinal symptoms. Furthermore, blood samples were drawn for analyses of biomarkers e.g. hemoglobin, blood glucose, cholesterol, liver parameters and vitamins. The participants with undiagnosed celiac seropositivity were matched by sex, age and study with four controls among the celiac disease antibody negative participants. RESULTS: We excluded, five participants with known celiac disease, resulting in a population of 16,771 participants. In this population 1% (169/16,771) had undiagnosed celiac seropositivity. There were no statistically significant differences in symptoms between cases and controls. Undiagnosed celiac seropositivity was associated with low blood cholesterol (< 5 mmol/L) and low hemoglobin (< 7.3 mmol/L for women and < 8.3 mmol/L for men). CONCLUSION: In this general population study, undiagnosed cases of celiac seropositivity did not have more symptoms than controls, confirming the diagnostic difficulties of celiac disease and the low prognostic value of symptoms for a diagnosis of celiac disease. Furthermore, decreased levels of cholesterol and/or hemoglobin in the blood were associated with undiagnosed celiac seropositivity.

Long-term Consequences of Undiagnosed Celiac Seropositivity.

INTRODUCTION: Diagnosed celiac disease (CD) is associated with lymphoproliferative malignancy and gastrointestinal cancer, but little is known about the long-term consequences of undiagnosed CD. We aimed to investigate long-term consequences of undiagnosed CD for mortality and incidence of cancer and other chronic diseases. METHODS: We screened biobank serum samples for immunoglobulin (Ig) A and IgG tissue transglutaminase (TTG) and IgG deamidated gliadin peptide in a study of 8 population-based cohort studies comprising 16,776 participants examined during 1976-2012 and followed with >99% complete follow-up in Danish nationwide registries until December 31, 2017, regarding vital status and incidence of diseases. Undiagnosed CD was defined as antibody positivity (IgA-TTG or IgG-TTG ≥ 7 U/mL and/or IgG deamidated gliadin peptide ≥ 10 U/mL) in individuals without a diagnosis of CD recorded in the National Patient Register. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by Cox regression analyses with age as the underlying time scale. RESULTS: The prevalence of undiagnosed CD was 1.0% with no statistically significant increase over time. Undiagnosed CD was associated with increased risk of cancer overall (HR, 1.57; 95% CI, 1.16-2.11), gastrointestinal cancer (HR, 2.33; 95% CI, 1.35-4.04), cancer of the uterus (HR, 3.95; 95% CI, 1.46-10.69), breast cancer (HR, 1.98; 95% CI, 1.02-3.82), head and neck cancer (HR, 3.12; 95% CI, 1.15-8.43), and cardiovascular disease (HR, 1.37; 95% CI, 1.01-1.85). We found no statistically significant association between undiagnosed CD and mortality (HR, 1.19; 95% CI, 0.87-1.61). DISCUSSION: Undiagnosed CD was associated with increased risk of cardiovascular disease and cancer suggesting that untreated CD has serious long-term health consequences not only affecting the gastrointestinal tract (see Visual Abstract, Supplementary Digital Content, http://links.lww.com/AJG/B566).

Biochemical Diagnosis of Bile Acid Diarrhea: Prospective Comparison With the 75Seleno-Taurohomocholic Acid Test.

INTRODUCTION: The diagnosis of bile acid diarrhea is often missed because the availability of the seleno-taurohomocholic acid (SeHCAT) test is limited. We aimed to compare the biomarkers 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19) with the SeHCAT test. METHODS: Patients with chronic diarrhea without intestinal resection referred for SeHCAT were prospectively recruited for this diagnostic accuracy study. Blood was sampled at fasting and after a stimulation meal with chenodeoxycholic acid. SeHCAT retention ≤10% defined bile acid diarrhea and >10% defined miscellaneous diarrhea. Receiver operating characteristics (ROC) were analyzed with SeHCAT as the gold standard. www.clinicaltrials.gov (NCT03059537). RESULTS: Patients with bile acid diarrhea (n = 26) had mean C4 of 30 ng/mL (95% confidence interval: 19-46) vs 8 (7-11; P < 0.001) in the miscellaneous diarrhea group (n = 45). Area under the ROC curve (ROCAUC) for C4 was 0.83 (0.72-0.93). C4 < 15 ng/mL had 85% (74%-96%) negative predictive value; C4 > 48 ng/mL had 82% (59%-100%) positive predictive value. Twenty patients had C4 values 15-48 ng/mL, of whom 11/20 had SeHCAT ≤10%. Median fasting FGF19 was 72 pg/mL (interquartile range: 53-146) vs 119 (84-240) (P = 0.004); ROCAUC was 0.71 (0.58-0.83). Stimulated FGF19 responses did not differ (P = 0.54). DISCUSSION: We identified C4 thresholds with clinically useful predictive values for the diagnosis of and screening for bile acid diarrhea in patients with chronic watery diarrhea. Further validation of the cutoff values with the placebo-controlled effect of sequestrant therapy is warranted (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B603).

Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial.

OBJECTIVE: To investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality. DESIGN: 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed. RESULTS: 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye. CONCLUSION: Compared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic low-grade inflammation. TRIAL REGISTRATION NUMBER: NCT01731366; Results.

Plasma Alkylresorcinols Reflect Gluten Intake and Distinguish between Gluten-Rich and Gluten-Poor Diets in a Population at Risk of Metabolic Syndrome.

BACKGROUND: Many patients with celiac disease experience difficulties in adherence to a gluten-free diet. Methods for testing compliance to a gluten-free diet are costly and cumbersome. Thus, a simple biomarker of gluten intake is needed in a clinical setting and will be useful for epidemiologic studies investigating wider effects of gluten intake. OBJECTIVE: The aim was to evaluate plasma total alkylresorcinol concentrations as a measure of gluten intake. METHODS: In this randomized, controlled, crossover intervention study in 52 Danish adults with features of the metabolic syndrome, we compared 8 wk of a gluten-rich and gluten-poor diet separated by a washout period of ≥6 wk. We measured fasting plasma concentrations of alkylresorcinols to determine if they reflected differences in gluten intake as a secondary outcome of the original study. In addition, we investigated in 118 Danish adults the cross-sectional association between self-reported gluten intake and plasma alkylresorcinols in the same and a similar study at baseline. We used mixed-model ANCOVA for examining treatment effects, a classification tree to determine compliance to the gluten-poor diet, and linear regression models for examining baseline correlation between plasma alkylresorcinol concentrations and gluten intake. RESULTS: Plasma total alkylresorcinols decreased more during the gluten-poor period (geometric mean: -124.8 nmol/L; 95% CI: -156.5, -93.0 nmol/L) than in the gluten-rich period (geometric mean: -31.8 nmol/L; 95% CI: -63.1, -0.4 nmol/L) (P < 0.001). On the basis of the plasma alkylresorcinol profile, we built a classification tree to objectively determine compliance and found an overall participant misclassification error of 3.9%. In the cross-sectional study we found a 5.6% (95% CI: 2.4%, 8.9%) increase in plasma total alkylresorcinols per 1-g increase in reported gluten intake (P < 0.001). CONCLUSION: We propose the use of plasma alkylresorcinols to monitor compliance to a gluten-free diet as well as to help investigations into the possible effects of gluten in the wider population. This trial was registered at www.clinicaltrials.gov as NCT017119913 and NCT01731366.

Screening for celiac disease in Danish adults.

OBJECTIVE: The prevalence of celiac disease (CD) as recorded in the Danish National Patient Registry is ∼50/100,000 persons. This is much lower than the reported prevalence of CD in other Nordic countries and underdiagnosis is suspected. Our aim was to estimate the prevalence of CD in a population-based study of Danish adults. METHODS: A total of 2297 adults aged 24-76 years living in the southwestern part of Copenhagen were screened for CD by immunoglobulin (Ig)A and IgG antibodies to transglutaminases and deamidated gliadin. IgA/IgG-positive participants were invited to a clinical evaluation, including biopsies, by a gastroenterologist. RESULTS: Of the invited 56 participants, 40 underwent a full clinical evaluation and 8 persons were diagnosed with CD; 2 of the 16 persons, who did not complete the clinical evaluation, were considered by experts to have probable CD. None of the above 56 participants had a known history of CD or a recorded diagnosis of CD in National Patient Registry. By combining cases of biopsy-proven CD (n = 8), probable CD (n = 2), and registry-recorded CD (n = 1), the prevalence of CD was estimated to be 479/100,000 (11/2297) persons (95% CI: 197-761). CONCLUSION: In this general adult population, the prevalence of CD as estimated by screening and clinical evaluation was 10 times higher than the registry-based prevalence of CD. Of 11 participants diagnosed with CD in our screening study, 10 were unaware of the diagnosis prior to the study. Thus, our study suggests that CD is markedly underdiagnosed in Danish adults.

The human thoracic duct is functionally innervated by adrenergic nerves.

Lymphatic vessels from animals have been shown to be innervated. While morphological studies have confirmed human lymphatic vessels are innervated, functional studies supporting this are lacking. The present study demonstrates a functional innervation of the human thoracic duct (TD) that is predominantly adrenergic. TDs harvested from 51 patients undergoing esophageal and cardia cancer surgery were either fixed for structural investigations or maintained in vitro for the functional assessment of innervation by isometric force measurements and electrical field stimulation (EFS). Electron microscopy and immunohistochemistry suggested scarce diffuse distribution of nerves in the entire vessel wall, but nerve-mediated contractions could be induced with EFS and were sensitive to the muscarinic receptor blocker atropine and the α-adrenoceptor blocker phentolamine. The combination of phentolamine and atropine resulted in a near-complete abolishment of EFS-induced contractions. The presence of sympathetic nerves was further confirmed by contractions induced by the sympathomimetic and catecholamine-releasing agent tyramine. Reactivity to the neurotransmitters norepinephrine, substance P, neuropeptide Y, acetylcholine, and methacholine was demonstrated by exogenous application to human TD ring segments. Norepinephrine provided the most consistent responses, whereas responses to the other agonists varied. We conclude that the human TD is functionally innervated with both cholinergic and adrenergic components, with the latter of the two dominating.

Prospective comparison of diagnostic tests for bile acid diarrhoea.

BACKGROUND: Bile acid diarrhoea is often missed because gold standard nuclear medicine tauroselcholic [75-Se] acid (SeHCAT) testing has limited availability. Empirical treatment effect has unknown diagnostic performance, whereas plasma 7α-hydroxy-4-cholesten-3-one (C4) is inexpensive but lacks sensitivity. AIMS: To determine diagnostic characteristics of empirical treatment and explore improvements in diagnostics with potential better availability than SeHCAT. METHODS: This diagnostic accuracy study was part of a randomised, placebo-controlled trial of colesevelam. Consecutive patients with chronic diarrhoea attending SeHCAT had blood and stool sampled. Key thresholds were C4 > 46 ng/mL and SeHCAT retention ≤10%. A questionnaire recorded patient-reported empirical treatment effect. We analysed receiver operating characteristics and explored machine learning applied logistic regression and decision tree modelling with internal validation. RESULTS: Ninety-six (38%) of 251 patients had SeHCAT retention ≤10%. The effect of empirical treatment assessed with test results for bile acid studies blinded had 63% (95% confidence interval 44%-79%) sensitivity and 65% (47%-80%) specificity; C4 > 46 ng/mL had 47% (37%-57%) and 92% (87%-96%), respectively. A decision tree combining C4 ≥ 31 ng/mL with ≥1.1 daily watery stools (Bristol type 6 and 7) had 70% (51%-85%) sensitivity and 95% (83%-99%) specificity. The logistic regression model, including C4, the sum of measured stool bile acids and daily watery stools, had 77% (58%-90%) sensitivity and 93% (80%-98%) specificity. CONCLUSIONS: Diagnosis of bile acid diarrhoea using empirical treatment was inadequate. Exploration suggested considerable improvements in the sensitivity of C4-based testing, offering potential widely available diagnostics. Further validation is warranted. CLINICALTRIALS: gov: NCT03876717.

Ultrastructure of interstitial cells in subserosa of human colon.

We studied the ultrastructure of interstitial cells in the subserosal/adventitial layer in human colon. An interstitial cell type with an ultrastructure intermediate between fibroblast-like cells (FLC) and interstitial cells of Cajal was identified (IC-SS). IC-SS had thin and flattened branching processes, most densely arranged close to the longitudinal muscle cells. Caveolae, bundles of intermediate filaments and membrane-associated dense bands, often with a patchy basal lamina, were characteristic. Secretory organelles (granular endoplasmic reticulum, smooth endoplasmic reticulum, Golgi, coated vesicles) were prominent. The IC-SS ultrastructure was different from that of FLC in the longitudinal layer, which had no caveolae and fewer intermediate filaments. Peg-and-socket junctions between IC-SS and between IC-SS and muscle cells were present, and IC-SS processes had close, selective appositions to muscle cells. Gap junctions were not observed. Small nerve bundles were abundant, but close contacts (<100 nm) between IC-SS or muscle cells and nerves were inconspicuous. Close appositions between IC-SS and mast cells were present; close relations to macrophages were not observed. The myoid features of IC-SS are thus more pronounced in comparison with FLC of other locations in the gastrointestinal muscle. The organization and ultrastructure may suggest a regulatory nature of IC-SS on the colonic muscle layers.

Identification of interstitial Cajal-like cells in the human thoracic duct.

Interstitial Cajal-like cells (ICLCs) are speculated to be pacemakers in smooth muscle tissues. While the human thoracic duct (TD) is spontaneously active, the origin of this activity is unknown. We hypothesized that ICLCs could be present in the TD and using histological techniques, immunohistochemistry and immunofluorescence we have investigated the presence of ICLCs, protein markers for ICLCs and the cellular morphology of the human TD. Transmission electron microscopy was employed to investigate ultrastructure. Methylene blue staining, calcium-dependent fluorophores and confocal microscopy were used to identify ICLCs in live tissue. Methylene blue stained cells with morphology suggestive of ICLCs in the TD. Immunoreactivity localized the ICLC protein markers c-kit, CD34 and vimentin to many cells and processes associated with smooth muscle cells (SMCs): coexpression of c-kit with vimentin or CD34 was observed in some cells. Electron microscopy analysis confirmed ICLCs as a major cell type of the human TD. Lymphatic ICLCs possess caveolae, dense bands, a patchy basal lamina, intermediate filaments and specific junctions to SMCs. ICLCs were ultrastructurally differentiable from other interstitial cells observed: fibroblasts, mast cells, macrophages and pericytes. Lymphatic ICLCs were localized to the subendothelial region of the wall as well as in intimate association with smooth muscle bundles throughout the media. ICLCs were morphologically distinct with multiple processes and also spindle shapes. Confocal imaging with calcium-dependent fluorophores corroborated cell morphology and localization observed in fixed tissues. Lymphatic ICLCs thus constitute a significant cell type of the human TD and physically interact with lymphatic SMCs.

Osteoporosis and bone fractures in patients with celiac disease: A nationwide cohort study.

Celiac disease (CD) is an autoimmune disease caused by an abnormal immune response triggered by ingestion of gluten. Treatment of CD is a lifelong gluten-free diet. Both diagnosed and undiagnosed CD has been found to be associated with reduced bone mineral density, which can lead to an increased risk of fractures. We therefore aimed to investigate the association of CD and the risk of fractures and osteoporosis in Denmark in a nationwide registry-based study. We identified all patients with CD (ICD-10 code K90.0) between 2000 and 2018 and included those with at least two contacts with a CD diagnosis. In total, 9397 CD patients and 93,964 randomly selected age- and sex-matched (1:10) references from the general population were identified. The overall hazard ratio (HR) of developing osteoporosis in CD patients compared with matches was 5.39 (95 % confidence interval (CI): 4.89, 5.95), however when excluding events of osteoporosis occurring within 12 months from the date of diagnosis the overall HR was reduced to 3.87 (95 % CI: 3.44, 4.33). The HR for major osteoporotic fractures was 1.37 (95 % CI: 1.25, 1.51) and for any fractures 1.27 (95 % CI: 1.18, 1.36). For osteoporosis, major osteoporotic fractures, and any fracture prior to diagnosis of CD the odds ratios comparing CD patients with matches were 4.32 (95 % CI: 3.64, 4.68), 1.29 (95 % CI: 1.21, 1.37) and 1.34 (95 % CI: 1.27, 1.41), respectively. Thus, this study showed an increased risk of osteoporosis and bone fractures among individuals with CD, both before and after diagnosis of CD. These results underline that the risk of osteoporosis should be considered in the clinical management of patients with CD and that early diagnosis and treatment could be important.

Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial.

BACKGROUND: Bile acid diarrhoea is a common but overlooked cause of chronic watery diarrhoea. Plasma 7α-hydroxy-4-cholesten-3-one (C4) is an alternative to the gold standard tauroselcholic [75Se] acid (SeHCAT) test. Low-certainty evidence supports sequestrant treatment, including colesevelam. We aimed to determine the efficacy and safety of colesevelam in bile acid diarrhoea. METHODS: In this randomised, double-blind, placebo-controlled, investigator-initiated phase 4 trial of the sequestrant colesevelam in bile acid diarrhoea (SINBAD), we enrolled consecutive patients aged 18-79 years without inflammatory bowel disease attending SeHCAT testing for suspected bile acid diarrhoea at four Danish secondary care centres. Participants were randomly allocated 1:1 to receive 12 days of treatment with colesevelam (overencapsulated tablets of 625 mg) or placebo, with the starting dose of two capsules twice daily and titrated to effect during the first 5 days of treatment. A pharmacist independent of the clinical investigators generated a randomisation list on the web page randomization.com using block randomisation (randomisation was not stratified). C4 and SeHCAT diagnostic results were blinded during treatment. We treated all patients with diarrhoea, with a daily mean of 3·0 or more bowel movements or 1·0 or more watery bowel movements (Bristol stool scale type 6 and 7). Remission was defined as the absence of both these criteria during treatment days 6-12. The primary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by C4 concentration greater than 46 ng/mL. A secondary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by SeHCAT retention of 10% or less. This trial is registered with ClinicalTrials.gov, NCT03876717. FINDINGS: Between Oct 25, 2018, and July 1, 2021, 168 patients were randomly assigned to receive colesevelam (n=84) or placebo (n=84). 41 patients had C4 concentration greater than 46 ng/mL (22 assigned to the colesevelam group and 19 to the placebo group). For the C4-defined primary outcome, 14 (64%) of 22 participants receiving colesevelam versus three (16%) of 19 participants receiving placebo achieved remission (adjusted odds ratio 9·1, 95% CI 1·9-62·8; p=0·011). For the SeHCAT-defined secondary outcome, 75 of the 168 participants had retention of less than 10% (37 assigned to the colesevelam group and 38 assigned to the placebo group); 22 (59%) of 37 participants receiving colesevelam achieved remission versus five (13%) of 38 participants receiving placebo (adjusted odds ratio 11·1, 95% CI 3·4-45·6; p=0·00020). There were no serious adverse events. Common adverse events were transient. For patients receiving colesevelam within the primary outcome population, five had abdominal pain, nine had bloating, and four had nausea. For patients receiving placebo, four had abdominal pain, four had bloating, and one had nausea. No participants with bile acid diarrhoea withdrew due to adverse events. INTERPRETATION: Colesevelam was superior to placebo at inducing remission of bile acid diarrhoea diagnosed with C4 concentration greater than 46 ng/mL. Secondary outcome data suggest similar efficacy treating SeHCAT-defined bile acid diarrhoea. Colesevelam was safe during the treatment. FUNDING: Fabrikant Vilhelm Pedersen og hustrus mindelegat; recommended by the Novo Nordisk Foundation.

Diagnostic Delay in Coeliac Disease: A Survey among Danish Patients.

Background: Coeliac disease affects around 1% of the population, although many cases remain undiagnosed. Underdiagnosis and diagnostic delay in coeliac disease may cause health complications and be a burden for both the patient and society. Casuistic reports indicate that the diagnostic delay may be significant in Danish patients. Aim: To investigate the diagnostic delay among Danish patients with coeliac disease. Methods: We performed a survey among coeliac disease patients to investigate the diagnostic delay. A web-based questionnaire was sent to all members of The Danish Coeliac Society. Results: The questionnaire was completed by 1,392 individuals with a diagnosis of coeliac disease (78.1% women; mean age: 42.8 years). The mean delay was 1.8 (SD 5.0) years from the first symptom to the first health care contact and 5.8 (SD 9.5) years from the first symptom to diagnosis; 18.6% of the participants reported a total diagnostic delay of more than 10 years. Among the patient-reported reasons for delay were misunderstandings, unspecific symptoms, and a lack of knowledge or focus on coeliac disease among the doctors. In total, 52.7% rated the time to diagnosis to have been "too long," and 20.1% were not satisfied with the diagnostic process. However, the majority were "to some extent" or "very" satisfied with the diagnostic process. Conclusion: We found evidence of a significant diagnostic delay among Danish patients with coeliac disease. This was primarily due to the delay from the time of first health care contact to the time of diagnosis. This study highlights the importance of raising awareness of coeliac disease among health care professionals.

Biochemical abnormalities among patients referred for celiac disease antibody blood testing in a primary health care setting.

To investigate possible biochemical abnormalities associated with celiac disease (CD) antibody positivity in a primary health care setting and thereby identify predictors that could potentially reduce diagnostic delay and underdiagnosis of CD. This observational cohort study included measurements of CD antibodies in the Copenhagen Primary Care Laboratory (CopLab) database from 2000 to 2015; CD antibody positivity was defined as tissue transglutaminase antibody IgA or IgG ≥ 7 kU/L and/or deamidated gliadin peptide antibody IgG ≥ 10 kU/L. Individuals with a prior diagnosis of CD were excluded. We examined differences between individuals with positive and negative CD antibody tests regarding the results of biochemical tests performed six months before and one month after the date of the CD antibody test. We identified 76,265 measurements of CD antibodies during 2000-2015, and 57,061 individuals met the inclusion criteria (706 antibody-positive and 56,355 antibody-negative). We found lower ferritin, hemoglobin, cobalamin and folic acid levels and higher levels of transferrin, ALAT (alanine transaminase), and alkaline phosphate among individuals with a positive CD antibody test. Furthermore, we illustrated more measurements below the sex-specific reference intervals for hemoglobin, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), ferritin, cobalamin and folic acid among individuals with a positive CD antibody test. This study identified several biochemical abnormalities associated with CD antibody positivity among individuals referred to CD antibody testing. The pattern of abnormalities suggested that micronutrient deficiencies were prevalent among CD antibody-positive individuals, confirming malabsorption as a sign of CD. These findings illustrate the possibility of reducing diagnostic delay and underdiagnosis of CD.

Crohn's disease of the colon: ultrastructural changes in submuscular interstitial cells of Cajal.

Interstitial cells of Cajal (ICC) at the submuscular border of the human colon (ICC-SMP) are the proposed pacemaker cells of the musculature. In patients with Crohn's disease (CD) of the colon, ICC-SMP showed characteristic cytological changes from controls. The changes comprised secondary lysosomes in connection with lipid droplets and cytoplasmic vacuoles or multiple empty, confluent and often outbulging vacuoles merging with cisterns of granular endoplasmic reticulum and clusters of glycogen granules. These changes were most pronounced in patients with macroscopical mucosal inflammation but were also demonstrable in uninvolved colonic segments. Relationships of ICC to other cells were undisturbed. The changes were selective to ICC-SMP, as glial cells, muscle cells and fibroblast-like cells at the submuscular border showed no cytological alterations compared with controls. Varicosities of the submuscular plexus were often empty and dilated. Fibroblast-like cells selectively encased macrophages and mast cells. The cytological changes in ICC-SMP in CD are thus similar to changes seen in ulcerative colitis and may be of pathophysiological significance with regard to the motility and sensory disturbances seen in patients with CD.

Crohn's disease: ultrastructure of interstitial cells in colonic myenteric plexus.

The role of the interstitial cells of Cajal (ICC) in chronic inflammatory bowel disease, i.e., ulcerative colitis (UC) and Crohn's disease (CD), remains unclear. Ultrastructural alterations in ICC in the colonic myenteric plexus (ICC-MP) have been reported previously in UC, but descriptions of ICC-MP and other interstitial cells in the myenteric region of the colon are lacking for CD. In the present study, we characterized the ultrastructure of interstitial cells, nerves, and glial cells in the myenteric region in Crohn's colitis (CC). In comparison with controls, varicosities of the myenteric bundles were dilated and appeared to be empty. Lipid droplets and lipofuscin-bodies were prominent in glial cells and neurons. ICC-MP were scanty but, as in controls, had caveolae, prominent intermediate filaments, cytoplasmic dense bodies, and membrane-associated dense bands with a patchy basal lamina. ICC-MP were similar in the various colonic regions. ICC-MP in CC showed no signs of degeneration or cytological changes. As in controls, fibroblast-like cells had abundant coated vesicles but lacked prominent intermediate filaments and caveolae. Macrophages also appeared as in controls. In comparison with ICC-MP in UC, the cytology of ICC-MP in CC were thus undisturbed. The ultrastructural differences between UC and CC might reflect pathophysiological differences of importance for understanding pathogenetic differences between CD and UC.

Ultrastructure of Cajal-like interstitial cells in the human detrusor.

The aim of this ultrastructural study was to examine the human detrusor for interstitial cells of Cajal (ICC)-like cells (ICC-L) by conventional transmission electron microscopy (TEM) and immuno-transmission electron microscopy (I-TEM) with antibodies directed towards CD117 and CD34. Two main types of interstitial cells were identified by TEM: ICC-L and fibroblast-like cells (FLC). ICC-L were bipolar with slender (0.04 microm) flattened dendritic-like processes, frequently forming a branching labyrinth network. Caveolae and short membrane-associated dense bands were present. Mitochondria, rough endoplasmic reticulum and Golgi apparatus were observed in the cell somata and cytoplasmic processes. Intermediate filaments were abundant but no thick filaments were found. ICC-L were interconnected by close appositions, gap junctions and peg-and-socket junctions (PSJ) but no specialised contacts to smooth muscle or nerves were apparent. FLC were characterised by abundant rough endoplasmic reticulum but no caveolae or membrane-associated dense bands were observed; gap junctions and PSJ were absent and intermediate filaments were rare. By I-TEM, CD34 gold immunolabelling was present in long cytoplasmic processes corresponding to ICC-L between muscle fascicles but CD117 gold immunolabelling was negative. Thus, ICC-like cells are present in the human detrusor. They are CD34-immunoreactive and have a myoid ultrastructure clearly distinguishable from fibroblast-like cells. ICC-L may be analogous to interstitial cells of Cajal in the gut.

Ultrastructure of interstitial cells of Cajal in myenteric plexus of human colon.

The role of the interstitial cells of Cajal (ICC) associated with the myenteric plexus (ICC-MP) as regulators of the motility of the colonic external muscle remains unclear. Ultrastructural studies of myenteric interstitial cells are lacking in human colon. We therefore characterized the distinctive ultrastructure of these cells in the myenteric region of the colon by transmission electron microscopy of the region between the main muscle layers in all parts of the colon in unaffected areas of resected specimens from nine adult human patients. ICC-MP were similar in various colonic regions and had myoid features such as scattered caveolae, prominent intermediate filaments, and cytoplasmic dense bodies. We found characteristic dense membrane-associated bands with a patchy basal lamina, invaginating cellular protrusions (peg and socket junctions) between ICC and between ICC and muscle cells, and close contacts (<100 nm) between ICC and nerves. No gap junctions were observed. Fibroblast-like cells (FLC) were abundant showing well-developed secretory organelles, including coated vesicles, but lacked prominent intermediate filaments and caveolae. FLC had a patchy basal lamina, and peg and socket junctions were observed between them. Macrophage-like cells frequently occurred in close apposition with FLC and, more seldomly, with ICC-MP. The ultrastructure of ICC and FLC in the myenteric region of the human colon thus differs characteristically, but significant overlaps in the ultrastructure between ICC and FLC might complicate any interpretation in pathological ultrastructural studies of the human colonic muscle layer.