Hujoel, Isabel A.

Goals: We aimed to evaluate symptom outcomes in those on a gluten-free diet during the 5 years after diagnosis. Background: Celiac disease is common; however, little is known about long-term symptom outcomes. Study: We performed a retrospective chart review on individuals with celiac disease followed at a tertiary referral center between 2012 and 2018. To minimize bias, strict inclusion/exclusion criteria were utilized. Only those with definitive biopsy-proven celiac disease, on a gluten-free diet, and with systematic follow-up were included. The standardized care at this center reduced the risk that decisions on testing and follow-up visits were determined by symptom status. Summary statistics were computed and generalized linear models with a logit link were used to associate the proportion of symptomatic visits with various covariates using R statistical programming. Results: Of the 1023 records reviewed, 212 met inclusion/exclusion criteria; 146 (69%) were female and the mean age at diagnosis was 43 (range: 11 to 84 y old). During follow-up, over 50% remained symptomatic, with many having the same symptoms that prompted the diagnosis. The only predictors for remaining symptomatic were female sex and younger age at diagnosis. Abnormal serology during follow-up and small bowel normalization were not predictive. Conclusions: In individuals with definitive celiac disease with systematic long-term follow-up in a Celiac Clinic, roughly half remained symptomatic despite a gluten-free diet. Many suffer from the same symptoms that prompted the diagnosis of celiac disease. Small bowel healing and abnormal serology in follow-up were not predictive of remaining symptomatic. These findings stress the importance of long-term care in celiac disease.

AbstractCeliac disease is a global disease requiring genetic susceptibility and gluten exposure to trigger immune‐mediated enteropathy. The effect of the degree of gluten‐containing grain availability on celiac disease prevalence is unknown. Our objective was to compare country‐based gluten availability to celiac prevalence using a systematic literature review. We searched MEDLINE, Embase, Cochrane, and Scopus until May 2021. We included population‐based serum screening with confirmatory testing (second serological study or small intestine biopsy) and excluded specific, high‐risk, or referral populations. We determined country‐specific gluten availability using the United Nations food balance for wheat, barley, and rye. Human leukocyte antigen (HLA) frequencies were obtained from allelefrequencies.net. The primary outcome was association between gluten‐containing grain availability and celiac disease prevalence. Generalized linear mixed models method with Poisson's link was used for analysis. We identified 5641 articles and included 120 studies on 427 146 subjects from 41 countries. Celiac disease prevalence was 0–3.1%, median 0.75% (interquartile range 0.35, 1.22). Median wheat supply was 246 g/capita/day (interquartile range 214.8, 360.7). The risk ratio (RR) for wheat availability on celiac disease was 1.002 (95% confidence interval [CI]: 1.0001, 1.004, P = 0.036). A protective association was seen with barley, RR 0.973 (95% CI: 0.956, 0.99, P = 0.003), and rye, RR 0.989 (95% CI: 0.982, 0.997, P = 0.006). The RR for gross domestic product on celiac disease prevalence was 1.009 (95% CI: 1.005, 1.014, P < 0.001). The RR for HLA‐DQ2 was 0.982 (95% CI: 0.979, 0.986, P < 0.001), and that for HLA‐DQ8 was 0.957 (95% CI: 0.950, 0.964, P < 0.001). In this geo‐epidemiologic study, gluten‐containing grain availability showed mixed associations with celiac disease prevalence.

AbstractContextThe World Health Organization set the recommended daily vitamin C intake, henceforth referred to as ascorbic acid (AA), on the basis of scurvy prevention. Double-blind AA depletion-repletion studies suggest that this recommended AA dose may be too low to prevent microvascular fragility.Objectives(1) To conduct a systematic review and meta-analysis of controlled clinical trials on whether AA supplementation leads to a reduced gingival bleeding tendency, a manifestation of microvascular fragility; and (2) to relate AA plasma levels to retinal hemorrhaging, another manifestation of microvascular fragility.Data sourcesData were reviewed from 15 trials conducted in 6 countries with 1140 predominantly healthy participants with measures of gingival bleeding tendency, and from the National Health and Nutrition Examination Survey (NHANES) III of 8210 US residents with measures of retinal hemorrhaging.ResultsIn clinical trials, AA supplementation reduced gingival bleeding tendency when estimated baseline AA plasma levels were &lt; 28 μmol/L (standardized mean difference [SMD], −0.83; 95%CI, −1.16 to −0.49; P &lt; 0.002). Supplementation with AA did not unequivocally reduce gingival bleeding tendency when baseline estimated AA plasma levels were &gt;48 μmol/L or unknown (respective standardized mean differences: −0.23, 95%CI, −0.45 to −0.01, P &lt; 0.05; and −0.56; 95%CI: −1.19 to 0.06, P &lt; 0.08). In NHANES III, prevalence of both retinal hemorrhaging and gingival bleeding tendency increased when AA plasma levels were within the range that protects against scurvy (11–28 μmol/L; respective prevalence ratios adjusted for age and sex: 1.47; 95%CI: 1.22–1.77; and 1.64; 95%CI: 1.32–2.03; P &lt; 0.001 for both).ConclusionConsistent evidence from controlled clinical trials indicates that setting human AA requirements based on scurvy prevention leads to AA plasma levels that may be too low to prevent an increased gingival bleeding tendency. Gingival bleeding tendency and retinal hemorrhaging coincide with low AA plasma levels and thus may be reflective of a systemic microvascular pathology that is reversible with an increased daily AA intake.

Goal: The goal of this study was to estimate the impact of verification bias on the diagnostic accuracy of immunoglobulin A tissue transglutaminase (IgA tTG) in detecting celiac disease as reported by an authoritative meta-analysis, the 2016 Comparative Effectiveness Review (CER). Background: Verification bias is introduced to diagnostic accuracy studies when screening test results impact the decision to verify disease status. Materials and Methods: We adjusted the sensitivity and specificity of IgA tTG reported by the 2016 CER with the proportion of IgA tTG positive and negative individuals who are referred for confirmatory small bowel biopsy. We performed a systematic review from January 1, 2007, to July 19, 2017, to determine these referral rates. Results: The systematic review identified 793 articles of which 9 met inclusion criteria (n=36,477). Overall, 3.6% [95% confidence interval (CI): 1.1%-10.9%] of IgA tTG negative and 79.2.2% (95% CI: 65.0%-88.7%) of IgA tTG positive individuals were referred for biopsy. Adjusting for these referral rates the 2016 CER reported sensitivity of IgA tTG dropped from 92.6% (95% CI: 90.2%-94.5%) to 57.1% (95% CI: 35.4%-76.4%) and the specificity increased from 97.6% (95% CI: 96.3%-98.5%) to 99.6% (95% CI: 98.4%-99.9%). Conclusions: The CER may have largely overestimated the sensitivity of IgA tTG due to a failure to account for verification bias. These findings suggest caution in the interpretation of a negative IgA tTG to rule out celiac disease in clinical practice. More broadly, they highlight the impact of verification bias on diagnostic accuracy estimates and suggest that studies at risk for this bias be excluded from systematic reviews.

Background and AimIrritable bowel syndrome (IBS) affects 12% of the population, and the evidence supporting current medical interventions is poor. There is increasing focus on the therapeutic benefit of diet and supplementation. We aim to compare dietary composition and hematologic and biochemical markers in those with and without IBS to determine potential targets for therapeutic supplementation.MethodsAll 17 national surveys between 1959 and 2019 were screened, and only 1, the Second National Health and Nutrition Examination Survey (NHANES II) (1976–1980), provided comprehensive data on IBS. We performed a cross‐sectional analysis of hematologic and biochemical markers and dietary composition of 12 295 individuals, aged 18–74, in NHANES II.ResultsIndividuals with IBS had significantly higher copper–zinc ratios (1.70vs1.55,P= 0.048) and were more likely to have ratios above 1.8 (odds ratio 1.79, 95% confidence interval 1.02–3.13), indicative of underlying copper–zinc imbalance. While more likely to report dietary avoidances, they had no other evidence of nutritional deficiencies. In addition, dietary recall showed that those with IBS consumed more calories (P= 0.02), were more likely to take vitamin supplements (P= 0.003), and that their macro and micronutrient intake was not significantly different.ConclusionsThe findings suggest that individuals with IBS should be screened for copper–zinc imbalance. Given zinc's role in the immune system, the “brain–gut” axis, and the gastrointestinal barrier, the identified copper–zinc imbalance may play a role in perpetuating the underlying pathophysiology of IBS. Further studies are needed to investigate this hypothesis and the potential role of therapeutic zinc supplementation.

INTRODUCTION: Irritable bowel syndrome (IBS) is common, affecting 12% of the population. However, the quality of evidence in support of current medical interventions has been rated as very low, and the majority of those with IBS report their symptoms as being unchanged or worsened over time. Diet is thought to play a significant role in IBS, and there is increasing focus on the therapeutic benefit of diet and supplementation. This study aims to compare dietary composition and serologic markers of nutritional status in those with and without IBS to determine potential targets for therapeutic supplementation. METHODS: All 17 national surveys between 1959 and 2019 were screened and only one, the Second National Health and Nutrition Examination Survey (NHANES II) (1976-1980), provided comprehensive data on IBS. We performed a cross-sectional analysis of serology and dietary composition of 12,295 individuals, aged 18 to 74 in NHANES II. Dietary composition was drawn from dietary recall questionnaires, and the diagnosis of IBS was based on self-reporting. RESULTS: Individuals with IBS had significantly higher copper-zinc ratios (1.70 versus 1.55, P = 0.048) and were more likely to have ratios above 1.8 (odds ratio 1.79, 95% confidence interval 1.02-3.13), suggestive of an underlying zinc deficiency. This deficiency may be due to their avoidance of milk, which was the largest source of dietary zinc in the study population. While they were significantly more likely to report dietary avoidances, they had no other serologic evidence of nutritional deficiencies. Additionally, dietary recall showed that they consumed significantly more daily calories ( P = 0.02), were more likely to take vitamin supplements ( P = 0.003) and that their macro and micronutrient intake was not significantly different. CONCLUSION: The findings suggest that individuals with IBS should be screened for zinc deficiency. Zinc deficiency may perpetuate the underlying pathophysiology of IBS and may contribute to the associated psychiatric conditions through zinc's role in the immune system, “brain-gut” axis, and gastrointestinal barrier integrity. This suggests that zinc supplementation may be a potential therapy both to mitigate underlying pathology as well as improve symptoms. Our findings should be confirmed in future studies, and the association of copper-zinc ratios with symptom severity, and the response of symptoms to supplementation could be investigated.

Linked ContentThis article is linked to Hujoel et al and Ellul papers. To view these articles visit https://doi.org/10.1111/apt.14625 and https://doi.org/10.1111/apt.14918.

SummaryBackgroundCoeliac disease is a substantially underdiagnosed disorder, with clinical testing currently guided by case finding.AimTo determine the presence of indications for diagnostic testing and frequency of clinical testing in undiagnosed coeliac disease.MethodsThis was a case‐control study of adults without prior diagnosis of coeliac disease. Undiagnosed cases were identified through sequential serology, and unaffected age‐ and gender‐matched controls were selected. Medical records were systematically reviewed for indications for and evidence of clinical testing.ResultsOf 47 557 adults, 408 cases of undiagnosed coeliac disease were identified. 408 serology negative matched controls were selected. Eight‐matched pairs were excluded, leading to 800 included individuals (61% female; median age 44.2 years). The odds of any indication for clinical testing were similar among undiagnosed coeliac disease and controls (odds ratio (OR) 1.18; 95% CI: 0.85‐1.63, P = 0.32). Most individual indications were not associated with serologic status. Exceptions to this include hypothyroidism, which was more likely in cases of undiagnosed coeliac disease, and dyspepsia and chronic diarrhoea, which were less likely. Cases of undiagnosed coeliac disease were more likely to develop osteoporosis (P = 0.005), dermatitis herpetiformis (P = 0.006), chronic fatigue (P = 0.033), thyroiditis (P = 0.003), autoimmune diseases (P = 0.008), and have a family member diagnosed with coeliac disease (P = 0.001).ConclusionThis study strongly suggests that current case finding is not effective in detecting undiagnosed coeliac disease. Individuals with undiagnosed coeliac disease were more likely than controls to develop indications for testing overtime. A more effective method for detection of coeliac disease is needed.