Rupa Mukherjee

Celiac Disease or Non-Celiac Gluten Sensitivity? An Approach to Clinical Differential Diagnosis

OBJECTIVES:Differentiating between celiac disease (CD) and non-celiac gluten sensitivity (NCGS) is important for appropriate management but is often challenging.METHODS:We retrospectively reviewed records from 238 patients who presented for the evaluation of symptoms responsive to gluten restriction without prior diagnosis or exclusion of CD. Demographics, presenting symptoms, serologic, genetic, and histologic data, nutrient deficiencies, personal history of autoimmune diseases, and family history of CD were recorded. NCGS was defined as symptoms responsive to a gluten-free diet (GFD) in the setting of negative celiac serology and duodenal biopsies while on a gluten-containing diet or negative human leukocyte antigen (HLA) DQ2/DQ8 testing.RESULTS:Of the 238 study subjects, 101 had CD, 125 had NCGS, 9 had non-celiac enteropathy, and 3 had indeterminate diagnosis. CD subjects presented with symptoms of malabsorption 67.3% of the time compared with 24.8% of the NCGS subjects (P<0.0001). In addition, CD subjects were significantly more likely to have a family history of CD (P=0.004), personal history of autoimmune diseases (P=0.002), or nutrient deficiencies (P<0.0001). The positive likelihood ratio for diagnosis of CD of a >2× upper limit of normal IgA trans-glutaminase antibody (tTG) or IgA/IgG deaminated gliadan peptide antibody (DGP) with clinical response to GFD was 130 (confidence interval (CI): 18.5–918.3). The positive likelihood ratio of the combination of gluten-responsive symptoms and negative IgA tTG or IgA/IgG DGP on a regular diet for NCGS was 9.6 (CI: 5.5–16.9). When individuals with negative IgA tTG or IgA/IgG DGP also lacked symptoms of malabsorption (weight loss, diarrhea, and nutrient deficiencies) and CD risk factors (personal history of autoimmune diseases and family history of CD), the positive likelihood ratio for NCGS increased to 80.9.CONCLUSIONS:On the basis of our findings, we have developed a diagnostic algorithm to differentiate CD from NCGS. Subjects with negative celiac serologies (IgA tTG or IgA/IgG DGP) on a regular diet are unlikely to have CD. Those with negative serology who also lack clinical evidence of malabsorption and CD risk factors are highly likely to have NCGS and may not require further testing. Those with equivocal serology should undergo HLA typing to determine the need for biopsy.

Colonoscopy surveillance after polypectomy may be extended beyond five years.

Objectives Colonoscopy surveillance interval data longer than 5 years are limited. We examined adenoma yield to identify factors that predict appropriate intervals for postpolypectomy surveillance greater than 5 years, including risk of advanced adenoma recurrence. Methods We identified patients with and without adenomas on an index colonoscopy who returned at 5 to 10 years for a follow-up colonoscopy. Multivariate logistic regression was used to identify variables that predict finding an adenoma on follow-up colonoscopy. Results Three hundred ninety-nine patients were identified with a follow-up colonoscopy at an interval of >5 years. Irrespective of surveillance interval, adenoma incidence occurred in 116 patients (29.1%) with 25 (6%) having advanced adenomas. Patients with nonadvanced adenomas on index colonoscopy had a similar risk of advanced adenoma on follow-up colonoscopy at 5 years versus 6 to 10 years, 5% versus 6.2% (P=0.39). The risk of advanced adenoma at 5 and 6 to 10 years in patients with a negative index colonoscopy was 7% versus 3.6% (P=0.15). Patients with an advanced adenoma at index colonoscopy had the highest rate of advanced adenoma detection at 5 years at 26%. Proximal polyp location (odds ratio 12.4, confidence interval 2.7-56.7) predicted advanced adenoma occurrence at 5 years. Conclusions Postpolypectomy colonoscopy intervals can be extended beyond 5 years in patients with nonadvanced adenomas. Our findings also support a rescreening interval of 5 to 10 years in patients with a negative index colonoscopy. Patients with an index advanced adenoma are at highest risk for recurrent advanced adenoma and should have repeat colonoscopy before a 5 years interval.

Patients With Celiac Disease Have a Lower Prevalence of Non–Insulin-Dependent Diabetes Mellitus and Metabolic Syndrome

BACKGROUND & AIMS We investigated whether risk for non-insulin-dependent diabetes mellitus (NIDDM) and metabolic syndrome are affected by celiac disease. We examined the prevalence of NIDDM and metabolic syndrome among adults with celiac disease, compared with matched controls. METHODS We assessed medical records of 840 patients with biopsy-proven celiac disease for diagnoses of NIDDM, hypertension, or hyperlipidemia; body mass index (BMI); lipid profile; and levels of glucose or glycosylated hemoglobin, to identify those with metabolic syndrome. Patients without celiac disease were matched for age, sex, and ethnicity (n = 840 controls). The prevalence of NIDDM and metabolic syndrome in the celiac disease cohort was compared with that of the controls and subjects included in the National Health and Nutrition Examination Survey. RESULTS Twenty-six patients with celiac disease (3.1%) had NIDDM compared with 81 controls (9.6%) (P < .0001). Similarly, the prevalence of metabolic syndrome was significantly lower among patients with celiac disease than controls (3.5% vs 12.7%; P < .0001). The mean BMI of patients with celiac disease was significantly lower than that of controls (24.7 vs 27.5; P < .0001). However, celiac disease was still associated with a lower risk of NIDDM, after controlling for BMI. CONCLUSIONS The prevalence of NIDDM and metabolic syndrome are lower among patients with celiac disease than in matched controls and the general population. These differences are not explained by differences in BMI. Studies are needed to determine the mechanisms by which celiac disease affects the risk for NIDDM and metabolic syndrome.

Factors governing long-term adherence to a gluten-free diet in adult patients with coeliac disease.

A strict gluten‐free diet is the cornerstone of treatment for coeliac disease. Studies of gluten‐free diet adherence have rarely used validated instruments. There is a paucity of data on long‐term adherence to the gluten‐free diet in the adult population.

Prevalence of Abnormal Liver Function Tests in Celiac Disease and the Effect of a Gluten-Free Diet in the US Population

OBJECTIVES:Guidelines recommend routine screening of liver function tests (LFTs) in patients diagnosed with celiac disease (CD). However, little is known about the prevalence of liver disorders in CD outside of Europe. Our aims were to estimate the prevalence of LFT abnormalities in CD and to evaluate the effect of a gluten-free diet (GFD) on LFTs.METHODS:Adult patients with biopsy-proven CD were identified from a prospectively maintained database and matched with healthy controls. LFT levels for women and men were defined as abnormal based on the Third National Health and Nutrition Examination Survey (NHANES III) criteria. Data on demographics, coexisting liver diseases, and laboratory work-ups including aspartate transaminase (AST) and alanine transaminase (ALT) values at the time of diagnosis and on a GFD were recorded. Subsequently, data from this cohort were compared with data from 7,789 individuals participating in the National Health and Nutrition Examination Survey, 2009–2010. Univariate logistic regression, Wilcoxon signed-ranks, Student’s t-test, χ2, and Fischer’s exact test were used for statistical analysis.RESULTS:In 463 CD patients with ALT or AST levels at the time of CD diagnosis, 40.6% had elevated LFTs compared with 24.2% of treated CD patients (P<0.001) and 16.6% of matched controls (P<0.001). Similarly, 36.7% of CD patients on the NHANES database had abnormal ALT values compared with 19.3% of non-celiac patients (P=0.03). Approximately, 78.6% of CD patients with elevated LFTs at diagnosis normalized LFTs on a GFD after a mean duration of 1.5±1.5 years.CONCLUSIONS:Forty percent of individuals will have elevated LFTs at CD diagnosis; however, the majority will normalize with standard CD therapy. LFTs should be checked in all patients with CD and coexisting liver disorder should be considered in patients whose LFTs have not improved within a year on a GFD.

Nondietary Therapies for Celiac Disease

Currently, the only available therapy for celiac disease is strict lifelong adherence to a gluten-free diet (GFD). Although safe and effective, the GFD is not ideal. It is frequently expensive, of limited nutritional value, and not readily available in many countries. Consequently, a need exists for novel, nondietary therapies for celiac disease. Based on the current understanding of celiac disease pathogenesis, several potential targets of therapeutic intervention exist. These novel strategies provide promise of alternative, adjunctive treatment options but also raise important questions regarding safety, efficacy, and monitoring of long-term treatment effect.

The carboxyl-terminal zinc-binding domain of the human papillomavirus E7 protein can be functionally replaced by the homologous sequences of the E6 protein

The carboxyl-terminus is necessary for the functional and structural integrity of the human papillomavirus (HPV) E7 oncoprotein. Since many mutations in this domain of E7 result in the formation of unstable proteins, we have evaluated the importance of this region by replacing it with structurally related domains derived from HPV E6 proteins. Biological analysis of these mutant chimeric E7/E6 proteins showed that they retained E7-specific biological activities including cooperation with the ras oncogene to transform primary baby rat kidney cells and transcriptional activation of an E2F responsive reporter plasmid. One of the chimeric proteins was impaired in its ability to physically disrupt pRB/E2F complexes in vitro suggesting that there are defined molecular determinants in the carboxyl-terminus of E7 for this activity. In contrast, none of these proteins exhibited E6-like properties including binding to p53 and/or degradation of associated proteins.

Celiac disease 2015 update: new therapies

Celiac disease (CD) is a chronic, small intestinal, immune-mediated enteropathy triggered by exposure to dietary gluten in genetically susceptible individuals. Currently, lifelong adherence to a gluten-free diet (GFD) is the only available treatment. However, GFD alone is not sufficient to relieve symptoms, control small intestinal inflammation and prevent long-term complications in many patients. The GFD has its challenges including issues related to adherence, lifestyle restrictions and cost. As a result, there is growing interest in and a need for non-dietary therapies to manage this condition. In recent years, different targets in the immune-mediated cascade of CD have been identified in clinical and pre-clinical trials for potential therapies. This review will discuss the latest non-dietary therapies in CD, including endopeptidases, modulators of enterocyte tight junctions and agents involved in gluten tolerization and immunomodulation. We will also discuss the potential implications of approved therapeutics on CD clinical practice.

Proinflammatory cytokine interferon‐γ and microbiome‐derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease

Coeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (Treg) are CD4+CD25++forkhead box protein 3 (FoxP3+) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 Δ2, cannot properly down‐regulate the Th17‐driven immune response. As the active state of CD has been associated with impairments in Treg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 Δ2 isoform over FL, while both isoforms were expressed similarly in non‐coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate‐producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)‐γ and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial‐derived metabolites.

Response to Aziz et al.

individuals specifi cally presenting with selfreported gluten sensitivity, a fi nding of LD in association with a positive celiac serology (tissue transglutaminase and / or endomysial antibodies) and correct HLA-DQ typing would be supportive of CD. However, recent reports have now suggested that LD may also occur in NCGS — that is, in cases of self-reported gluten sensitivity but with negative serology ( 7 ). Th e clinical evaluation performed by Kabbani et al. did not identify any such patient, and hence this form of presentation was not considered as part of the subsequent diagnostic model proposed. Nevertheless, previous studies (including those listed in Table 1 ) have noted LD in the context of negative serology ( 8 ). Identifi cation of such individuals is important because, although they may fulfi l the current criteria for NCGS, other causations need to be excluded, including CD, given that a proportion will be HLADQ positive and demonstrate endomysial antibodies on the duodenal culture medium despite the negative serology ( 8 – 11 ). We feel that the algorithm proposed should incorporate such diagnostically challenging patients, considering them as an “ indeterminate ” group. In summary, the data shown suggest that self-reported gluten sensitivity is an international concept. We would like to take this opportunity to congratulate Kabbani et al. for their signifi cant eff orts in exploring this complex clinical entity and providing a platform from which a consensus can now be reached.