The Rising Incidence and Poor Outcomes of Enteropathy-Associated T-Cell Lymphoma.

INTRODUCTION: Enteropathy-associated T-cell lymphoma (EATL) is associated with celiac disease. With the rising prevalence of celiac disease, we hypothesized that the prevalence of EATL is also increasing. METHODS: We used the Surveillance, Epidemiology, and End Results database, which is a population-based US cancer surveillance program. We used the ICD-0-3 code 9717/3 to identify patients with EATL diagnosed between 2000 and 2020. Incidence rates were calculated using the SEER*Stat software, and annual percent change was calculated using the Joinpoint software. Log-rank tests were used to evaluate for significant difference in survival curves between groups. A Cox proportional hazards regression model was used for continuous variables and quantifying association strength of predictors. RESULTS: A total of 463 cases of EATL were identified (273 male, 190 female) with a median age of 65 (range 23-90+) years. Most of the cases were at an advanced stage at diagnosis and were treated with a combination of surgery and chemotherapy. The median survival time was 6 months. The 2000-2020 age-adjusted incidence rate per 100,000 people was 0.014, and the incidence increased between 2000 and 2020, with an annual percent change of 2.58 ( P < 0.05). Increased age at diagnosis and lack of treatment had significant impacts on survival while sex, year of diagnosis, race, and time between diagnosis and treatment had no significant impact on survival. DISCUSSION: There was a significant increase in the incidence of EATL in the United States between 2000 and 2020. Survival in this cancer remains poor and unchanged over the past 2 decades.

Investigating the role of iron status in the development of coeliac disease: a Mendelian randomisation study.

OBJECTIVE: The environmental trigger behind the increasing prevalence of coeliac disease is not known. One suggested cause is iron deficiency, which is common in coeliac disease. We aimed to evaluate this possible association with Mendelian randomisation (MR), which under certain assumptions can suggest a causal relationship. DESIGN: We conducted a two-sample MR study examining the relationship between single nucleotide polymorphisms (SNPs) associated with iron status and the presence of coeliac disease. The SNPs were drawn from a meta-analysis of three genome-wide association studies (GWAS). The association between these SNPs and coeliac disease was assessed using GWAS summary statistics from the UK Biobank. This consists of 336 638 white British individuals, 1855 with coeliac disease. We performed an MR Egger test for pleiotropy and assessed the plausibility of the assumptions of MR to evaluate for possible causality. RESULTS: There were four SNPs strongly associated with systemic iron status. These were not associated with known risk factors for coeliac disease. All four SNPs were available in the UK Biobank coeliac disease summary statistics. Harmonising exposure and outcome associations, we found that higher iron status was negatively associated with risk of coeliac disease (OR per 1 SD increase in serum iron: 0.65, 95% CI 0.47 to 0.91). Leave-one-out analyses had consistent results, and no single SNP drove the association. All three assumptions of MR appeared plausible. CONCLUSION: We found that genetically lower iron levels were associated with an increased risk of coeliac disease. Our findings highlight a potential opportunity for coeliac disease prevention.

Symptom Outcomes of Celiac Disease in Those on a Gluten-free Diet.

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.

Relationship between gluten availability and celiac disease prevalence: A geo-epidemiologic systematic review.

Celiac 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.

The Use of Deep Snare Biopsies to Diagnose Cronkhite-Canada Syndrome.

Cronkhite-Canada syndrome is a rare sporadic polyposis syndrome that presents with dermatologic and neurologic symptoms in addition to nutritional deficiencies. It can mimic alternate pathologies, such as Menetrier disease, making adequate histologic sampling with deep snare biopsies necessary for tissue comparison. We present a case report of Cronkhite-Canada syndrome that demonstrates the importance of deep tissue sampling for adequate diagnosis and treatment initiation.

Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge.

BACKGROUND & AIMS: Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury. METHODS: This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine. RESULTS: Fifty patients were randomized, and 43 patients completed the study (IMGX003, n = 21; placebo, n = 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P = .231), 0.96 vs 3.29 (bloating, P = .204), and 0.02 vs 3.20 (tiredness, P = .113). The 3 × 2-week trend line significance values for these symptoms, respectively, were P = .014, .030, and .002. CONCLUSIONS: IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number: NCT03585478).

Latitude and Celiac Disease Prevalence: A Meta-Analysis and Meta-Regression.

BACKGROUND & AIMS: The latitudinal gradient effect is described for several autoimmune diseases including celiac disease in the United States. However, the association between latitude and global celiac disease prevalence is unknown. We aimed to explore the association between latitude and serology-based celiac disease prevalence through meta-analysis. METHODS: We searched MEDLINE, Embase, Cochrane, and Scopus databases from their beginning through June 29, 2018, to identify screening studies that targeted a general population sample, used serology-based screening tests, and provided a clear location from which we could assign a latitude. Studies were excluded if sampling was based on symptoms, risk factors, or referral. Study selection and data extraction were performed by independent reviewers. The association measures between latitude and prevalence of serology-based celiac disease were evaluated with random-effects meta-analyses and meta-regression. RESULTS: Of the identified 4667 unique citations, 128 studies were included, with 155 prevalence estimates representing 40 countries. Celiac disease was more prevalent at the higher latitudes of 51° to 60° (relative risk [RR], 1.62; 95% CI, 1.09-2.38) and 61° to 70° (RR, 2.30; 95% CI, 1.36-3.89) compared with the 41° to 50° reference level. No statistically significant difference was observed at lower latitudes. When latitude was treated as continuous, we found a statistically significant association between CD prevalence and latitude overall in the world (RR, 1.03, 95% CI, 1.01-1.05) and a subregional analysis of Europe (RR, 1.05; 95% CI, 1.02-1.07) and North America (RR, 1.1; 95% CI, 1.0-1.2). CONCLUSIONS: In this comprehensive review of screening studies, we found that a higher latitude was associated with greater serology-based celiac disease prevalence.

The Role of Copper and Zinc in Irritable Bowel Syndrome: A Mendelian Randomization Study.

Irritable bowel syndrome (IBS) has been associated with copper and zinc imbalance and a zinc-deficient diet. Mendelian randomization was used in this study to evaluate if genetically determined copper and zinc levels play a causal role in the development of IBS. Three single-nucleotide polymorphisms (SNPs; rs1175550, rs2769264, and rs2769270) associated with erythrocyte copper levels, and 3 SNPs associated with erythrocyte zinc levels (rs11638477, rs1532423, and rs2120019) in the Australian Twin Study (1993-1996 and 2001-2005) were used as instrumental variables for levels of these metals. The association of these SNPs with IBS was tested using summary statistics computed from data on 340,331 individuals from the UK Biobank, 5,548 of whom had IBS (2006-2010). Genetically predicted high serum copper levels were associated with a lower risk of IBS (odds ratio = 0.89; 95% confidence interval: 0.80, 0.98). Genetically predicted, high serum zinc levels were nonsignificantly associated with a higher risk of IBS (odds ratio = 1.06; 95% confidence interval: 0.95, 1.18). Sensitivity analysis did not suggest the presence of pleiotropy. These results suggest that high erythrocyte copper levels may be protective against IBS development. Targeting higher levels, therefore, may provide an avenue to reduce the likelihood of IBS development in high-risk individuals.

Bleeding tendency and ascorbic acid requirements: systematic review and meta-analysis of clinical trials.

CONTEXT: The 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 SOURCES: Data 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. RESULTS: In clinical trials, AA supplementation reduced gingival bleeding tendency when estimated baseline AA plasma levels were < 28 µmol/L (standardized mean difference [SMD], -0.83; 95%CI, -1.16 to -0.49; P < 0.002). Supplementation with AA did not unequivocally reduce gingival bleeding tendency when baseline estimated AA plasma levels were >48 µmol/L or unknown (respective standardized mean differences: -0.23, 95%CI, -0.45 to -0.01, P < 0.05; and -0.56; 95%CI: -1.19 to 0.06, P < 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 < 0.001 for both). CONCLUSION: Consistent 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.

Estimating the Impact of Verification Bias on Celiac Disease Testing.

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.

Nutritional status in irritable bowel syndrome: A North American population-based study.

BACKGROUND AND AIM: Irritable 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. METHODS: All 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. RESULTS: Individuals with IBS had significantly higher copper-zinc ratios (1.70 vs 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), 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. CONCLUSIONS: The 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.

Refractory Celiac Disease.

PURPOSE OF REVIEW: To review the epidemiology, pathophysiology, diagnosis, management, and prognosis of refractory celiac disease, with a specific emphasis on recent literature. RECENT FINDINGS: While the pathophysiology of type I refractory celiac disease remains unclear, there have been advances in the understanding of the pathophysiology of type II refractory celiac disease. This has included recognition of the significant role of interleukin-15 and somatic mutations in JAK1 or STAT3 in the proliferation of aberrant T cells. This in turn has led to potential novel therapies targeting these factors, one of which has reached the clinical trial stage. The morbidity and mortality associated with type II refractory celiac disease remain significant; however, recent advances in the understanding of the pathophysiology of this condition have led to potential therapeutic options that should be investigated.

Celiac Disease: Clinical Features and Diagnosis.

The presentation in celiac disease is shifting from the classical malabsorptive presentation to more nonclassical presentations, requiring clinicians to maintain a high level of suspicion for the disease and to be aware of the possible extraintestinal manifestations. The diagnosis of celiac disease is guided by initial screening with serology, followed by confirmation with an upper endoscopy and small intestinal biopsy. In some pediatric cases, biopsy may be avoided.

Tropheryma whipplei Infection (Whipple Disease) in the USA.

BACKGROUND: Whipple disease (WD) is an infection caused by the bacterium Tropheryma whipplei (TW). Few cases have been reported in the USA. AIMS: To report on the demographics, clinical manifestations, diagnostic findings, treatment, and outcomes of TW infection. METHODS: Cases of TW infection diagnosed from 1995 to 2010 were identified in three US referral centers and from 1995 to 2015 in one. Definite classic WD was defined by positive periodic acid-Schiff (PAS) staining and probable WD by specific positive TW polymerase chain reaction (PCR) of intestinal specimens. Localized infections were defined by a positive TW PCR result from samples of other tissues/body fluids. RESULTS: Among the 33 cases of TW infections, 27 (82%) were male. Median age at diagnosis was 53 years (range 11-75). Diagnosis was supported by a positive TW PCR in 29 (88%) and/or a positive PAS in 16 (48%) patients. Classic WD was the most frequent presentation (n = 18, 55%), with 14 definite and 4 probable cases. Localized infections (n = 15, 45%) affected the central nervous system (n = 7), joints (n = 4), heart (n = 2), eye (n = 1), and skeletal muscle (n = 1). Blood PCR was negative in 9 of 17 (53%) cases at diagnosis. Ceftriaxone intravenously followed by trimethoprim and sulfamethoxazole orally was the most common regimen (n = 23, 70%). Antibiotic therapy resulted in clinical response in 24 (73%). CONCLUSIONS: TW infection can present as intestinal or localized disease. Negative small bowel PAS and PCR do not exclude the diagnosis of TW infection, and blood PCR is insensitive for active infection.

Sex Difference in Celiac Disease in Undiagnosed Populations: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: A higher proportion of female vs male patients receive a diagnosis of celiac disease. Little is known about sex-based differences in the prevalence of celiac disease in undiagnosed populations. We aimed to address this knowledge gap with a systematic review and meta-analysis. METHODS: We searched MEDLINE, Embase, Cochrane, and Scopus databases through 2017 for studies of screen-detected or undiagnosed celiac disease. Our final analysis included studies that included screening and confirmatory tests (either second serologic analysis or a small intestine biopsy) and provided information on the sex of participants. Studies were excluded if they were performed with specific, high-risk, or referral populations. The primary outcome was the percentage of undetected celiac disease among female and male patients. RESULTS: We identified 4070 articles and analyzed data from 87. Our meta-analysis comprised data from 291,969 study participants. The pooled prevalence of undetected celiac disease in female participants was 0.589% (95% CI, 0.549%-0.629%) and in male participants was 0.415% (95% CI, 0.343%-0.487%). The risk of undetected celiac disease was higher among female than male participants (relative risk [RR], 1.42; 95% CI, 1.27-1.57; P < .00001). The I2 was 5% (low heterogeneity among studies). In subgroup analyses, the RR of celiac disease for girls vs boys was 1.79 (95% CI, 1.44-2.22; P < .00001; I2 = 18%), the RR for female vs male blood donors was 1.13 (95% CI, 0.76-1.69; P = .54; I2 = 0), and the RR for women vs men with villous atrophy was 1.38 (95% CI, 1.07-1.79; P = .01; I2 = 0). CONCLUSIONS: In a systematic review and meta-analysis, we found a higher risk for celiac disease in women than men in an undiagnosed populations (identified through general population screening). The increased risk for celiac disease among girls and women should be considered for screening, diagnosis, and management strategies.

Epstein-Barr Virus-Positive Mucocutaneous Ulcer in an Immunosuppressed Patient.

Immunosuppressive medications, frequently used to treat inflammatory bowel disease, have been linked to the development of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD). We describe a case of an EBV-positive mucocutaneous ulcer involving the palate in an elderly woman with inactive Crohn's disease. This patient had been on high-dose azathioprine for a decade. Following diagnosis of her LPD and discontinuation of azathioprine, her oral ulcers resolved completely.

Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies.

Enteropathies can be overwhelming for clinicians. There is a wide spectrum of diseases involved; their effect on patients can be severe; and their underlying cause can be obscure. In this article, we outline a practical approach to enteropathies that are most common and not to be missed and is applicable to general and specialist physicians.