Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten‐free diet

Mahadev, SriHari; Murray, Joseph A.; Wu, Tsung Teh; Chandan, Vishal S.; Torbenson, M. S.; Kelly, Ciarán P.; Mäki, Markku; Green, P. H. R.; Adelman, Donna; Lebwohl, Benjamin

doi:10.1111/apt.13988

Cited by 67 publications

(77 citation statements)

References 35 publications

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“…Under‐reporting the severity of mucosal injury in follow‐up biopsies is concerning for patients and treating physicians, but in this study was rectified by re‐cutting biopsies with poorly orientated tissue sections. A further limitation of our findings might be that we did not consider potential drug‐induced enteropathy to occur in our study subjects, for example subjects using Olmesartan, proton pump inhibitors, nonsteroidal anti‐inflammatory drugs or selective serotonin reuptake inhibitors …”

Section: Discussionmentioning

confidence: 99%

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

et al. 2020

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Summary Background The prevalence and severity of duodenal injury in coeliac disease patients controlled on a gluten‐free diet is unclear. Aims To use quantitative histology to assess duodenal injury in treated coeliac disease. Methods Quantitative histology in pre‐treatment duodenal biopsies collected in clinical trials assessing an investigational immunotherapy for coeliac disease was analysed. Morphometric readings were converted to Marsh classifications. Results Ninety‐three patients had duodenal biopsies. For well‐oriented sections of second part biopsies, six (6%) patients were classified as Marsh 0 or 1, 30 (33%) as Marsh 2 and 56 (60%) as Marsh 3a or 3b. In second part biopsies from 78 seronegative patients on gluten‐free diet >2 years, 27 (35%) were Marsh 2 and 45 (58%) were Marsh 3a or 3b. Distal compared to proximal duodenal biopsies had significantly higher villus height to crypt depth ratios (median, third part: 2.1 vs bulb: 1.4; P < 0.0001) and higher intraepithelial lymphocyte density (44 vs 30; P = 0.0002). The sum of paired villus height and adjacent crypt depth measurements was correlated strongly with villus height (rs = 0.82, P < 10−10). At least one biopsy was graded Marsh 3a or worse in all 26 patients who had serial biopsies from the bulb, first, second and third part, but was overlooked in 20 patients by subjective histology. Conclusions Quantitative histology in well‐oriented biopsy sections reveals villus atrophy in the majority of patients with coeliac disease who appear well controlled on gluten‐free diet. Standardisation of biopsy collection, processing and evaluation could substantially improve the value of follow‐up biopsies in coeliac disease.

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Section: Discussionmentioning

confidence: 99%

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

et al. 2020

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“…The findings of our study are limited to the day of a substantial gluten exposure when nausea predominates and are informative of acute symptoms within hours of gluten ingestion. Duodenal injury related to chronic gluten exposure is found in many patients with coeliac disease on a gluten‐free diet . Therefore, IBS‐like symptoms being common in coeliac disease may be a nonspecific effect of mucosal inflammation rather than directly linked to gluten‐mediated immune activation .…”

Section: Discussionmentioning

confidence: 99%

Masked bolus gluten challenge low in FODMAPs implicates nausea and vomiting as key symptoms associated with immune activation in treated coeliac disease

Daveson

Tye–Din

Goel³

et al. 2019

Aliment Pharmacol Ther

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Summary Background In patients with coeliac disease, FODMAPs in gluten‐containing foods, and participant anticipation of a harmful (‘nocebo’) effect, may contribute to acute symptoms after gluten challenge. Aim To establish acute gluten‐specific symptoms linked to immune activation in coeliac disease Methods We included 36 coeliac disease patients on a gluten‐free diet receiving placebo in the RESET CeD trial. Double‐blind, bolus vital wheat gluten (~6‐g gluten protein) and sham challenges low in FODMAPs were consumed 2 weeks apart. Assessments included daily Coeliac Disease Patient Reported Outcome (CeD PRO) symptom scores (0‐10), adverse events and serum interleukin‐2 (baseline and 4 hours). Results Median CeD PRO score for nausea increased most (sham: 0 vs gluten: 5.5; P < .001). Apart from tiredness (1 vs 4, P = .005) and headache (0 vs 2, P = .002), changes in other symptoms were small or absent. Only nausea increased significantly in occurrence with gluten (11% vs 69%, P < .001). Without nausea, only tiredness and flatulence were common after gluten. Nausea (6% vs 61%, P < .001; median onset: 1:34 hours) and vomiting (0% vs 44%, P < .001; 1:51 hours) were the only adverse events more common with gluten than sham. Interleukin‐2 was always below the level of quantitation (0.5 pg/mL) at baseline, and after sham. Interleukin‐2 was elevated after gluten in 97% of patients (median fold‐change: 20), and correlated with severity of nausea (rs = .49, P = .0025) and occurrence of vomiting (P = .0005). Conclusions Nausea and vomiting are relatively specific indicators of acute gluten ingestion, and correlate with immune activation. IBS‐like symptoms without nausea are unlikely to indicate recent gluten exposure.

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“…The literature on coeliac disease and depression and anxiety is abundant, but so far we are unaware of any studies exploring the association with mucosal healing. One prior study of coeliac disease participants in a clinical trial found that antidepressant use was associated with an increased prevalence of persistent villous atrophy, though depressive symptoms were not measured and clinical trial participants may not be representative of the general coeliac population …”

Section: Discussionmentioning

confidence: 99%

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

Ludvigsson

Lebwohl

Chen

et al. 2018

Aliment Pharmacol Ther

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Summary Background Coeliac disease has been linked to anxiety and depression. However, their association with mucosal healing is unknown. Aim To examine the relationship between anxiety, depression and mucosal healing in coeliac disease. Methods 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. Results 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). Conclusion 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.

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Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten‐free diet

Cited by 67 publications

References 35 publications

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

Masked bolus gluten challenge low in FODMAPs implicates nausea and vomiting as key symptoms associated with immune activation in treated coeliac disease

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

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