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.

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.

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.

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.

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.

Diagnosis of bile acid diarrhoea by fasting and postprandial measurements of fibroblast growth factor 19.

BACKGROUND: A deficiency in the ileal hormone fibroblast growth factor 19 (FGF19) has been described in patients with bile acid diarrhoea (BAD), but fasting FGF19 levels have insufficient diagnostic power. We assess whether single postprandial sampling of FGF19 has greater discriminative value than fasting FGF19 for detection of BAD and we evaluate the reproducibility of fasting FGF19. MATERIALS AND METHODS: Twenty-six patients consecutively referred to Se homocholic acid retention test (SeHCAT) were included. Serum FGF19 was measured after an overnight fast and again 1 h postprandially and again in the fasting state 1 week later. RESULTS: Nine of 26 patients had SeHCAT less than 10% and fasting FGF19 was lower [median 62 pg/ml, interquartile range (IQR): 47-67] than in the 17 diarrhoea controls with SeHCAT at least 10% (median 103 pg/ml, IQR: 77-135, P=0.006). Postprandial FGF19 in BAD patients (61 pg/ml, IQR: 48-69) was similar to fasting values (P=0.59) and increased insignificantly in diarrhoea controls (137 pg/ml, IQR: 88-182; P=0.25). The difference in postprandial FGF19 between patients with BAD and diarrhoea controls was highly significant (P<0.001). CONCLUSION: The difference in serum FGF19 between groups of patients with BAD and diarrhoea controls is amplified postprandially. Within each group, the difference between fasting and postprandial FGF19 was not statistically significant. Further investigations are warranted on stimulated FGF19 response to elucidate its role in BAD.

Celiac disease: diagnosis and treatment.

This national clinical guideline approved by the Danish Society for Gastroenterology and Hepatology describes the diagnosis and treatment of celiac disease (CD) in adults. CD is a chronic immune-mediated enteropathy of the small intestine triggered by the ingestion of gluten-containing proteins, which are found in wheat, rye, and barley. The disease prevalence is 0.5-1.0%, but CD remains under-diagnosed. The diagnosis relies on the demonstration of lymphocyte infiltration, crypt hyperplasia, and villous atrophy in duodenal biopsies. Serology, malabsorption, biochemical markers, and identification of specific HLA haplotypes may contribute to CD diagnosis. Classical CD presents with diarrhoea and weight loss, but non-classical CD with vague or extraintestinal symptoms is common. The treatment for CD is a lifelong gluten-free diet (GFD), which, in the majority of patients, normalises the small intestinal mucosa and absorption. Adherence to a GFD usually requires dietary advice from a clinical dietician. The monitoring of antibody levels and malabsorption markers is crucial during follow-up and allows for early treatment of disease complications. Important complications include osteoporosis, iron and vitamin deficiencies, and enteropathy-associated T-cell lymphoma.

Serological testing for celiac disease in adults.

BACKGROUND AND AIM: We present a systematic review on the performance of currently available methods for serological diagnosis of celiac disease (CD) and the role of human leukocyte antigen (HLA) typing. OBJECTIVE: A literature survey was conducted using PubMed, MeSH database, Web of Science as well as manual searches. RESULTS: Tissue transglutaminase antibodies (tTG) (IgA) (tested in nine studies) show sensitivities and specificities in the range of 0.76-0.968 and 0.909-0.98, and deamidated gliadin peptide (DGP) (IgA and IgG) (tested in eight studies) show sensitivities and specificities in the range of 0.69-0.984 and 0.903-1. Endomysial antibodies (EMA) (tested in five studies) show sensitivities and specificities in the range of 0.61-0.937 and 0.98-1, respectively. Combination assays (tested in three studies) using DGP + tTG and DGP (IgA + IgG) show sensitivities and specificities in the range of 0.87-1 and 0.8-1, respectively. HLA DQ2/DQ8 may be necessary for the development of CD-HLA DQ2 in particular. A possible close correlation may also exist between CD and HLA-G. CONCLUSION: DGP and tTG for serological testing for CD show equivalent diagnostic performance. More studies with, in particular, DGP alone and in combination with tTG are necessary before a firm recommendation can be made. HLA typing to exclude CD may still be controversial. It still seems premature to diagnose celiac disease in adults based on serology alone.

Bile acid malabsorption or disturbed intestinal permeability in patients treated with enzyme substitution for exocrine pancreatic insufficiency is not caused by bacterial overgrowth.

INTRODUCTION: In some patients with severe exocrine pancreatic insufficiency, enzyme replacement therapy will not lead to clinical improvement or reduction of steatorrhea. Therefore, other mechanisms separately or in interplay with reduced enzyme secretion might be responsible for malabsorption in these patients. AIMS: To evaluate the prevalence of bacterial overgrowth, bile acid absorption capacity, and intestinal permeability in a group of patients with well-characterized exocrine pancreatic insufficiency. METHODOLOGY: Eleven men with severe exocrine pancreatic insufficiency, of whom 10 were receiving enzyme replacement therapy, were studied. The prevalence of bacterial overgrowth was evaluated by means of a hydrogen and methane breath test with glucose. Gamma camera scintigraphy after intake of 75Se-homocholic acid taurine (75Se-HCAT) was used to evaluate bile acid absorption capacity. Intestinal permeability was assessed from urine excretion of ingested 14C-mannitol and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA), and these data were compared with results for 10 age-matched healthy men. RESULTS: No patients had abnormal breath hydrogen or methane concentrations after glucose intake. Abdominal retention of 75Se-HCAT was reduced in three of the patients. The patients had lower urine excretion of 14C-mannitol than the control subjects, whereas no difference was revealed in urine excretion of 99mTc-DTPA. CONCLUSION: Bile acid absorption and small intestinal permeability might be affected in patients with exocrine pancreatic insufficiency who receive treatment with enzyme supplementation. The prevalence of bacterial overgrowth seems to be low among these patients and does not explain the findings.