Medscape (Medical Professionals' Continuing Ed site) Celiac Disease/Gluten Sensitivity articles
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New Article:
Optimizing the Diagnosis of Celiac Disease
Michelle Shui Yee Lau and David S. Sanders
Academic Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, UK
Correspondence to
Dr Michelle Shui Yee Lau, Academic Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, S102JF Sheffield, UK. Tel: +44 11 4226 1179; e-mail: michellelau@doctors.org.uk
Curr Opin Gastroenterol. 2017;33(1):173-180.
this article is 7 pages long so I will cut some for the sake of brevity.
Purpose of review The diagnostic approach in celiac disease is continuously evolving as our understanding of its pathophysiology improves. This review aims to provide a summary of contemporary work that supports optimization of the diagnosis of this common yet underdiagnosed condition.
Recent findings The recently updated National Institute of Clinical Excellence and European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines and the contentious biopsy-free diagnostic approach will be discussed. We will review the evidence advocating optimal biopsy techniques such as single bite biopsy and controversial bulb biopsy sampling to increase diagnostic yield. Recent data providing phenotypical characterization and clinical outcomes of celiac subtypes such as potential celiac disease, seronegative celiac disease and ultrashort celiac disease will be covered. We will present emerging evidence on novel case finding strategies with point of care tests. Promising novel markers for celiac disease such as serum intestinal fatty acid binding protein and in-vitro gluten challenge will be included.
Summary Recent work has demonstrated the clinical significance of the celiac disease subtypes, emphasizing the importance of careful diagnosis and recognition. There is a move toward a less invasive and perhaps more cost-effective diagnostic approach in celiac disease, but duodenal biopsy remains the gold standard at present for all adults and the majority of pediatric patients.
Celiac disease is a common yet underdiagnosed immune-mediated small intestinal enteropathy triggered by gluten in genetically susceptible individuals, with an approximately 1% prevalence in the United States and beyond.[1–3] A recent meta-analysis found a celiac disease seroprevalence of 1.6% in Asia (Iran, Turkey, Israel and India).[4] Similar figures are observed in population screening studies in Argentina (0.95% biopsy-proven celiac disease),[5] Malaysia (1.25% seroprevalence)[6] and Saudi Arabia (1% biopsy-proven celiac disease).[7] However, epidemiological studies found that up to 75% of patients are unrecognized,[8,9] leading to a poorer quality of life[10] and complications such as malnutrition, osteoporosis and small bowel lymphoma. Continuous efforts are being made to improve the detection of celiac disease.
Celiac disease manifests itself in a wide array of signs and symptoms which can be nonspecific. The 2015 National Institute of Clinical Excellence (NICE) guidance has highlighted that unexplained neuropathies such as ataxia are now indications for which serological testing is recommended.[11] Gluten ataxia accounts for 40% of all sporadic ataxias, and is characterized by positive IgA/IgG antigliadin antibodies and triggered by gluten in genetically susceptible people, with a mean age of onset of 53 years. Up to 40% of patients with gluten ataxia have evidence of enteropathy, yet interestingly, they often have no gastrointestinal symptoms. A gluten-free diet (GFD) can improve or halt the progression of neurological symptoms in most patients.[12]
The most comprehensive meta-analysis (n = 9275) of the relationship between irritable bowel syndrome (IBS)-type symptoms and celiac disease showed that the prevalence of celiac disease was significantly higher in IBS patients, with a pooled odds ratio (OR) for biopsy-proven celiac disease vs. controls of 4.48.[13] On the contrary, despite gastroesophageal reflux being a common symptom in celiac disease (34%), reflux was found to be negatively associated with celiac disease in a large prospective study (OR 0.12, P < 0.0001).
The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines for celiac disease were updated in 2012, incorporating contemporary diagnostic approaches.[15] ESPGHAN newly defined celiac disease as an immune-mediated systemic disorder rather than sole enteropathy triggered by gluten, with both intestinal and extra-intestinal manifestations. There is also a shift from histological confirmation being the gold standard, to relying more on serological testing and human leukocyte antigen (HLA) typing in the diagnostic process in certain patients.
HLA Genotyping
HLA genotyping can be valuable in equivocal diagnoses, usually in patients with seronegative villous atrophy, those already on a GFD who are unwilling or unable to undergo a gluten challenge, and those who refuse a gastroscopy. HLA genotyping was shown to provide the highest diagnostic yield (60%) in patients with raised intraepithelial lymphocytes (IELs) and normal TTG, whereas the yield was lowest in those with villous atrophy (16.4%) or positive TTG (14.3%).[22] The absence of HLA DQ2 and DQ8 virtually excludes celiac disease, with an NPV of more than 99%. However, for patients with a high clinical suspicion of celiac disease, certain HLA DQ2.5 alleles, either in cis or trans configuration, should be checked as these can be seen in celiac disease although rare.
Seronegative Celiac Disease
Seronegative celiac disease (SNCD) occurs in 1.7–15% of the celiac population.[23–25] SNCD can result from impaired immunoregulation such as IgA deficiency, common variable immunodeficiency, and those who are on immunosuppressants. It can also occur early in celiac disease,[26] late in the disease[27] or in patients who have placed themselves on a GFD prior to testing. Recent work by Volta et al.[25] compared the clinical characteristics between seropositive and seronegative celiac disease (total n = 810), and found that SNCD patients were older at diagnosis (49 vs. 36 years, P < 0.005) and had significantly more frequent typical symptoms such as diarrhea (100 vs. 34%, P < 0.001). SNCD was also associated with more severe villous atrophy (67 vs. 36%) and coexisting autoimmune diseases. These findings echo those reported by Salmi et al.,[24] who also found that transglutaminase 2 autoantibodies (TG2) deposited in the small bowel mucosa despite seronegativity in SNCD patients. The authors indicated that in SNCD, celiac antibodies are bound to intestinal TG2 with considerably high avidity, which occurs in long-standing immune reaction, rendering the antibodies not able to enter the circulation to cause seropositivity. SNCD is thus speculated to be associated with long standing, more severe celiac disease.
SNCD requires careful diagnosis with the support of HLA DQ2/DQ8 presence and a response to a GFD after excluding other causes of seronegative villous atrophy (SNVA). A large retrospective analysis of 200 cases of SNVA revealed that 31% were due to celiac disease, 27% of infective cause and 18% of idiopathic cases where 72% spontaneously resolved without any intervention. Intriguingly, nonwhite ethnicity was significantly associated with SNVA (OR 10.8, P = 0.003), and 66% of nonwhite patients with SNVA had an infective cause.[28]
Patients on a Self-imposed Gluten-free Diet
With the rapid expansion of the gluten-free market, increasing number of people who report gluten sensitivity present to clinicians having been on a self-imposed GFD. This poses diagnostic difficulties, as the conventional approach of a 6-week challenge of 10 g gluten/day is often intolerable for these individuals. However, recent data provided evidence that a shorter, lower dose gluten challenge was already sufficient to induce serological and histological changes in most celiac disease patients (3 g gluten/day for 2 weeks[29] and 10 g gluten/day for 18 days[14]). In particular, Leffler et al.[29] showed that a 3 g gluten challenge/day led to an increase in IgA-TTG or IgA/IgG-DGP titers above the ULN in 65% patients within 28 days, and Marsh 3 villous atrophy in 68% patients within 14 days. These findings may ease the burden of gluten challenge especially for patients who find the conventional 6-week challenge intolerable.
There is a paucity of data pertaining to the natural history and long-term outcomes of potential celiac disease (PCD), defined by positive serology and HLA genotype without villous atrophy. The latest prospective follow-up study demonstrated a 10.5% prevalence of PCD (77 of 735) within their celiac disease cohort.[30] Their diagnosis of PCD was defined as positive EMA and TTG, HLA DQ2 and/or DQ8 and Marsh 0–1 duodenal histology. This study reinforces the fact that most adult PCD patients are symptomatic (79%), and the majority present atypically with anemia, osteoporosis and irritable bowel, mirroring other study findings.[31,32] Over a median of a 3-year follow-up period, all symptomatic patients on a GFD had symptomatic, clinical and serological improvement. For the 16 asymptomatic PCD patients who stayed on a gluten containing diet, biannual serological titers fluctuated in five patients and one developed villous atrophy. These findings suggest that there is a beneficial role for a GFD in symptomatic PCD patients. For asymptomatic PCD, a gluten-containing diet with regular follow-up may be the appropriate management. Further studies with longer follow-up periods are required to validate these results.
Recent studies have shown that a bulb biopsy in addition to four biopsies in the second part of the duodenum increased the yield of celiac disease detection by 10–18%,[34,39,40] and such practice is recommended by the latest guidelines.[15,41,42]
Continued in next post.....
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Continued from previous post:
Ultrashort Celiac Disease
Apart from the patchy topographical variation of mucosal injury in celiac disease, it is evident that in some patients, villous atrophy is confined only to the bulb for reasons not known.[33,37,47] It is hypothesized that the gluten load is highest in the bulb as it is the first site in the small intestine to be reached by dietary gluten. More recently, Mooney et al.[39] reported the largest prospective study investigating the clinical phenotype and outcome of ultrashort celiac disease (USCD), that is celiac disease with villous atrophy limited to the bulb. The prevalence of USCD was 9.7% among the celiac disease cohort (total celiac disease prevalence 19.4%, 268 of 1378). Patients with USCD were found to be younger (37.3 vs. 42.0, P = 0.03), had lower TTG titers (mean 6.8 vs. 12.9, P = 0.001) and less frequently presented with diarrhea (3.8 vs. 24.1%, P < 0.0001) and nutritional deficiency (13.6 vs. 31.5%, P = 0.007) compared with conventional celiac disease. After a median of 16 months of a GFD, TTG levels of USCD patients significantly decreased and symptoms improved in the majority. The authors concluded that USCD may be an early or limited form of celiac disease, given the milder clinical phenotype and infrequent nutritional deficiencies. It is conceivable that patients diagnosed with 'potential celiac disease' or 'false positive serology' may actually have USCD if bulb biopsy was taken. This study adds to the importance of including bulb biopsy in the histological evaluation to avoid delayed or missed diagnoses.
Endoscopic Technologies
Endoscopic technologies for the visualization of duodenal villi have been reported with superior sensitivities compared with standard white light endoscopy, such as chromoendoscopy,[57,58] narrow band imaging (NBI),[59–61] water immersion technique,[62,63] I-scan (virtual chromoendoscopy),[64] confocal laser endomicroscopy[65,66] and magnification endoscopy.[67,68] However, these techniques have not been widely adopted because of the high prevalence populations in most studies, potentially falsely elevating their reported sensitivities. A recent large study assessed the utility of high definition endoscopy with or without I-scan in lower prevalence populations in two UK centers. They found that I-scan did not provide any additional benefit in the detection of celiac disease when high definition endoscopy was used compared with non high definition endoscopy (P = 0.47) (sensitivities: high definition endoscopy 85.7%, high definition endoscopy with I-scan 75% and non high definition endoscopy 41.6%).[69] Three other recent studies examined the value of NBI and magnification endoscopy compared with standard white light endoscopy. The sensitivities ranged between 84.4 and 100%, although the celiac disease prevalence was again high in all three studies (16–48.6%), limiting the generalizability of these findings.[59–61]
Point of Care Tests
Several point of care tests (POCTs) for celiac disease have been developed in the past decade, but they have not yet gained widespread acceptance. These POCTs use lateral flow immunochromatography to detect celiac antibodies and provide rapid results within 10 min. Most studies delivered promising results similar to serology, but common limitations include high celiac disease prevalence populations,[70,71] positive ascertainment bias where only individuals with positive antibodies underwent duodenal biopsies[72–75] and some studies measuring the POCT performance against serology rather than duodenal biopsies.[76,77] The latter two methodological flaws meant that false negative cases may be missed, elevating the reported sensitivities of the POCTs.
The only head-to-head trial comparing three commercially available POCTs in the UK was published recently. The study showed that the diagnostic accuracy of Simtomax, which detects IgA/IgG-DGP, significantly outperformed the other two POCTs (Biocard and Celiac Quick Test, both detect IgA-TTG) (P = 0.008 and 0.03, respectively) when tested on 55 patients referred with positive EMA. The sensitivities were 94.4, 72.2 and 77.8%, respectively. The authors then evaluated Simtomax in 508 unselected patients attending for a gastroscopy using duodenal biopsies as the reference standard in all patients. Simtomax was found to offer comparable diagnostic performance (sensitivity, specificity, PPV and NPV of 95.6, 40.9, 20.0 and 98.4%, respectively) to TTG serology, although the celiac disease prevalence was high at 13.4%.[78] Further POCT studies in low pretest populations are required to validate these results.
Apart from the convenience of being a finger prick test with rapid results, they may also prove to be cost-effective. A recent study showed that serology was only available in one-third of patients with anemia undergoing a gastroscopy despite the recommended guidelines, committing clinicians to often take routine duodenal biopsies, which is an expensive way of case detection. The authors demonstrated that when Simtomax was used in the endoscopy setting for patients with anemia (n = 133), it had 100% sensitivity and NPV in detecting celiac disease when measured against duodenal histology in all individuals. Thus, unnecessary biopsies could be avoided in those with a negative Simtomax test, leading to considerable cost savings. Larger studies are needed to substantiate these findings.
A recent proof-of-concept study demonstrated the utility of using the POCT, Simtomax, in 15 community pharmacies across the UK as a case finding tool for individuals at risk of celiac disease. The positive Simtomax rate was 9.6% (52 of 551), suggesting that this is a potentially feasible strategy involving allied healthcare professionals, with high patient satisfaction and positive feedback from the pharmacies involved.[80] Further work is needed to include follow-up duodenal biopsies for individuals with positive Simtomax, to fully elucidate the effectiveness of this novel case finding approach.
Novel Markers of Celiac Disease
Intestinal Fatty Acid Binding Protein
Recent studies have shown serum intestinal fatty acid binding protein (I-FABP) to be a sensitive marker of enterocyte damage in celiac disease. Two retrospective case–control studies of 68 children[81] and 237 adults[82] found that I-FABP levels were significantly higher in celiac disease compared with controls (median 458 vs. 20 pg/ml in children, P < 0.001 and median 691 vs. 178 pg/ml in adults, P < 0.001) and correlated with the severity of villous atrophy. After 12 weeks of a GFD, I-FABP levels rapidly normalized in 80% children with celiac disease. In contrast, for adults, I-FABP concentrations declined with a GFD (up to 3 years) but not to normal levels despite resolution of villous atrophy. This supports the fact that mucosal recovery in adults seems to be slower and incomplete.[83,84] More recently, I-FABP levels have been found to be an early marker of gluten exposure in celiac disease patients, with a significant rise during a 2-week gluten challenge, correlating with IEL count.[85] This could potentially be a useful surrogate marker for dietary adherence, which is currently lacking.
In-vitro Gluten Challenge
In-vitro exposure of duodenal biopsy specimens to gluten has been examined. Tortora et al.[85,86] found that the inflammatory marker HLA-DR was highly sensitive (area under receiver operating characteristic curve = 0.92–0.99) in detecting celiac disease, (in treated celiac disease, untreated celiac disease and gray cases with discordant serology and histology) at both 3 and 24 h of in-vitro incubation with gliadin compared with controls (total n = 337). If validated, this noninvasive diagnostic method could prove to be valuable in difficult cases.0 -
Medscape Coverage from
Digestive Disease Week (DDW) 2017
Enzyme Supplement Protects Gluten-sensitive Patients
Damian McNamara
May 19, 2017
CHICAGO — The prolyl endoprotease enzyme derived from Aspergillus niger might help people with a gluten sensitivity who unintentionally consume wheat or other grains avoid troublesome gastrointestinal symptoms, a small study suggests.
The enzyme, known as AN-PEP and marketed as Tolerase G by DSM in the United States, "actually works," said lead investigator Julia König, PhD, from Örebro University in Sweden. "There are a lot of enzymes on the market, but this functions in the stomach where the pH is acidic. Often enzymes don't work in this environment."
However, "you cannot use this enzyme to treat or prevent celiac disease," she cautioned here at Digestive Disease Week (DDW) 2017. A gluten-free diet is the only treatment, she said.
In a previous study Dr König was involved in, researchers demonstrated that AN-PEP breaks down gluten after an intragastrically infused liquid meal in healthy volunteers (Aliment Pharmacol Ther. 2015;42:273-285).
In their current randomized placebo-controlled crossover study, Dr König and her colleagues assessed the ability of AN-PEP to degrade gluten after a normal meal in people with gluten sensitivity.
The 18 participants self-reported gluten sensitivity and there was no confirmation of celiac disease.
On three separate visits, investigators collected gastric and duodenal aspirates with a multilumen nasoduodenal-feeding catheter. Participants then consumed a porridge containing gluten, approximately 0.5 g, in the form of two crumbled wheat cookies. They also consumed two tablets, containing AN-PEP (either 160,000 PPi or 80,000 PPi) or placebo.
Investigators collected stomach and duodenal aspirates over the course of 3 hours.
Gluten concentrations in the stomach and in the duodenum were significantly lower in both the high- and low-dose AN-PEP groups than in the placebo group.
Table. Mean Gluten Concentrations After Gluten Consumption
Aspirates (mg × min/mL) High-Dose AN-PEP Low-Dose AN-PEP Placebo P Value
Stomach 31 31 218 .001
Duodenum 12 8 65 .015
Gluten was degraded by 81% in the high-dose group and by 87% in the low-dose group before the meal reached the small intestine.
Dr König was asked during a press briefing whether participants were able to discern a difference in symptoms between the three treatment groups.
"We did not find a difference, but it was quite an invasive procedure," she replied. "We placed an NG tube through the nose and they were fasting overnight, so they already had GI symptoms due to that, in addition to the gluten they consumed, which was very little."
An advantage of the AN-PEP enzyme is that it works in the acidic environment of the stomach, which is not true for all enzymes, she explained.
We are not suggesting they can gorge on a whole bowl of pasta or pizza.
Despite the promise shown in this study, the enzyme is meant only for the unintentional consumption of gluten. "We are not suggesting they can gorge on a whole bowl of pasta or pizza. Even a small amount of gluten can cause harm in these patients," Dr König pointed out.
Enzyme Seems to Work Quickly
"The researchers showed that they can reduce the amount of gluten in the stomach substantially, and it seems to work fairly quickly," said Joseph Murray, MD, from the Mayo Clinic in Rochester, Minnesota.
"This is proof that it can degrade gluten in the stomach. That has not been done before," he told Medscape Medical News. However, it might not be useful as a rescue strategy, he pointed out.
"You have to take it right away. Many people who accidentally ingest gluten only realize that hours later, when they develop symptoms, at which point the food has probably already passed through the stomach," he explained.
The US Food and Drug Administration does not review the safety or efficacy of dietary supplements, and AN-PEP falls into that category, Dr Murray added. "But is it likely to cause harm? I kind of doubt it."
The researchers are planning a follow-up study to compare the effects of AN-PEP on specific symptoms in people with gluten sensitivity, Dr König reported.
Dr König and Dr Murray have disclosed no relevant financial relationships.
Digestive Disease Week (DDW) 2017: Abstract Su1137. Presented May 7, 2017.
Follow Medscape Gastroenterology on Twitter @MedscapeGastro and Damian McNamara @MedReporter
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Higher Risk for Celiac Disease in Diabetic Children
By Anne Harding
August 01, 2017
Celiac disease (CD) is more common in young people with type 1 diabetes than in diabetes-free kids, although how often the two conditions occur together varies in different countries, a new study finds.
“Celiac disease is not uncommon in type 1 diabetes, and regular screening is important,” the study’s lead author Dr. Maria Craig, from UNSW Medicine in Kensington, New South Wales, Australia, told Reuters Health by email.
Shared genetic risk is the major reason why CD is more common in type 1 diabetes patients, she added.
About 5 percent of people with type 1 diabetes have CD, compared to about 1 percent of the overall population, Craig and her colleagues note in their report in Diabetes Care, online June 29.
To see if this is true uniformly around the world, they looked at the prevalence of CD in four different registries of type 1 diabetes patients in Germany/Austria, the U.S., the UK and Australasia. The analysis included data from 2013 and 2014 on 52,721 children and teens under age 18.
Overall, 3.5 percent of the young people with diabetes in the study had CD, and the prevalence ranged from 1.9 percent in the U.S. to 7.7 percent in Australia. Girls were more likely to have CD than boys, at 4.3 percent versus 2.7 percent, respectively. On average, the children who had CD had been diagnosed with diabetes when they were 5.4 years old, compared to diagnosis at age 7 for children without CD.
While blood sugar control was just as good for the children with CD as for those without CD, the study found that children with CD were likely to be shorter.
“While the overall difference was modest, some children demonstrated important differences in height, highlighting the importance of early diagnosis and treatment,” Craig said.
SOURCE: http://bit.ly/2vPYsxP
Diabetes Care 2017.
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More new stuff from 2017: It's a PDF on studies and their conclusions re: GF and links to fibromyalgia as well as other diseases involving chronic pain.
https://researchgate.net/profile/Rossella_Talotta/publication/273783874_Algo-dysfunctional_syndromes_A_critical_digest_of_the_recent_literature/links/5810be3c08aee15d4914f66f.pdf
Only a couple pages long plus another of study references.0 -
New Medscape Sept 26/17
Intraepithelial Lymphocyte Count Distinguishes Celiac Disease From Normal Mucosa
By Will Boggs MD (Reuters Health Information)
NEW YORK (Reuters Health) - The intraepithelial lymphocyte (IEL) count in duodenal mucosa can be used to distinguish celiac disease from normal mucosa, with an optimal cutoff of 25 IEL/100 enterocytes, according to a case-control study.
"We achieved the confidence that IEL counts performed on cheap and conventional H and E-stained material provide optimal results in routine histological examinations and that using more-sophisticated CD3/gamma-delta immunostained sections would be recommended only in more-complex cases that require using specific markers,” Dr. Kamran Rostami from Milton Keynes University Hospital, in the UK, told Reuters Health by email. “We hope this reassures busy histopathologists that simple is best - especially those working in difficult or under-resourced settings worldwide.”
An increased population of IEL has been recognized as a hallmark of celiac disease for more than 50 years, but the literature lacks a definitive cutoff point to confirm the diagnosis.
Dr. Rostami and colleagues from 19 laboratories in 8 countries used H and E-stained biopsy specimens to determine IEL counts on 198 patients with celiac disease and 203 controls without celiac disease.
The mean IEL count was 54/100 enterocytes in celiac disease and 13/100 enterocytes in specimens from controls, according to the September 11 Gut online report.
IEL counts overlapped in 56 biopsies, representing 14% of the total specimens.
“The existence of a significant IEL numerical overlap between individuals with healthy small bowels and celiac disease was the most surprising finding,” Dr. Rostami said. “This is because no definitive definition of a ‘normal’ IEL count has ever been published in the existing literature so far. As a result, and in contrast to previous belief, the IEL were shown to be not different (so called bimodal) in disease and individuals with healthy bowel. This has never been demonstrated before.”
ROC curve analysis identified 25 IEL/100 enterocytes as the optimal cutoff for diagnosing celiac disease. This yielded 99.0% sensitivity, 93.1% specificity, and an overall accuracy of 99.5% (area under the curve).
With this cutoff, 3 women with celiac disease in this sample would have been false negatives and 12 controls would have been false positives.
IEL populations did not differ significantly among celiac disease biopsies graded as IIIa, IIIb, or IIIc.
“These data provide evidence for the lack of the validity of this sub-classification, whose abandonment would provide less work for pathologists concerned with celiac disease diagnosis,” Dr. Rostami said.
“We were very excited with the outcome of our analysis when we were able to conclude this study would make the diagnostic process of celiac disease easier and less expensive,” he said.
SOURCE: http://bit.ly/2hoEu6Q
Gut 2017.
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bmjopengastro.bmj.com/content/4/1/e000159Clinical and genetic profile of patients with seronegative coeliac disease: the natural history and response to gluten-free diet
Maria Pina Dore1,2, Giovanni Mario Pes1, Ivana Dettori1, Vincenzo Villanacci3, Alessandra Manca4, Giuseppe Realdi1
Author affiliations
Abstract
Objectives Patients with clinical, genetic and histological features of coeliac disease (CD), but negative for serological markers, pose a significant clinical problem. The aim of this study was to outline a specific profile, and to evaluate the natural history and response to gluten-free diet (GFD) of patients with seronegative CD.
Methods Patients with duodenal mucosa damage Marsh I, II and III stages, HLA DQ2/DQ8 haplotype and clinical features suggestive of CD, but negative for CD serology, were defined as seronegative CD patients. Other common causes of duodenal mucosa damage were excluded. HLA–DR and DQ genotype/haplotype between all Marsh stages of patients with seronegative and seropositive CD were compared. Clinical features, laboratory testing and histological findings were evaluated after a GFD and a gluten rechallenge. A long follow-up period was available.
Results 48 patients fulfilled diagnostic criteria over a 4-year period. Clinical phenotype and HLA−DR and DQ frequencies between patients with seronegative and seropositive CD was similar. However, Marsh I stage was more prevalent in seronegative patients (42% vs 22%; p<0.05). After a 1-year GFD trial, clinical symptoms, histological features and laboratory testing improved in 40 patients and worsened in those who underwent a 6-months gluten challenge. Five patients with seronegative CD (25%) experienced the occurrence of autoimmune diseases during a median follow-up of 133 months (range 72–192).
Conclusions Patients with seronegative CD did not display a specific profile. They benefitted from GFD as patients with seropositive CD. Waiting for more sensitive serological markers, the diagnosis of seronegative CD remains a diagnosis of exclusion.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
http://dx.doi.org/10.1136/bmjgast-2017-000159
First paragraphs of a much longer study paper with all references/links at the end.0 -
Finally more on Celiac Disease and Gluten sensitivity in my inbox.What Did Gastroenterologists Learn in the Past 12 Months That PCPs Should Know?
Lauri R. Graham; Laurie Scudder, DNP, NP; Joanna M. Pangilinan, PharmD
DISCLOSURES June 04, 2018
Unmasking Celiac Disease
An analysis of data from the Explorys database, which aggregates electronic health record data from over 35 million people enrolled in 26 major integrated healthcare systems in the United States, reported some surprising findings about celiac disease. The report https://medscape.com/viewarticle/889005, presented at the World Congress of Gastroenterology, revealed that the incidence of celiac disease was calculated at 0.22%, lower than the 1%-2% range previously estimated, a finding that the researchers attribute to underdiagnosis. They also found a significant association between celiac disease and 13 other autoimmune disorders. In fact, of the autoimmune conditions they looked at, with the exception of primary biliary cholangitis, all were found to be associated with celiac disease to some degree. A table in the article lists the prevalence of diagnoses in people with and without celiac disease.0 -
Digestive Disease Week Conference News:Experimental Drug May Protect Celiac-Disease Patients From Inadvertent Gluten Exposure
By Megan Brooks
June 01, 2018
NEW YORK (Reuters Health) - An experimental monoclonal antibody (AMG 714) may help protect patients with celiac disease from developing symptoms such as gut pain and diarrhea after inadvertent exposure to gluten, according to a proof-of-concept study.
But the drug did not show a significant effect on villous-height-to-crypt-depth ratio, the primary endpoint, researchers report.
The study, a phase 2a, placebo-controlled trial, was presented during a press briefing May 21 ahead of a presentation June 4 at Digestive Disease Week (DDW) 2018 in Washington, D.C.
"It is virtually impossible for celiac-disease patients to completely avoid gluten permanently and this leads to many patients on a gluten-free diet being inadvertently exposed to gluten," study chief Dr. Francisco Leon from Celimmune in Bethesda, Maryland, told the briefing. About 30% to 50% of all patients on a gluten-free diet continue to have signs and symptoms of gluten exposure, leading to reduced quality of life, he noted.
AMG 714 blocks interleukin-15, an important mediator of celiac disease, and "offers hope of relief for celiac disease patients who are inadvertently exposed to gluten," said Dr. Leon.
The study lasted 12 weeks and included 60 patients with celiac disease who were randomly allocated to AMG 714 (150 mg or 300 mg) or matching placebo given by subcutaneous injection six times over 10 weeks.
A subset of 49 patients received a high-dose gluten challenge of about 2.5 g/day for 10 weeks. Another 11 patients, who showed mucosal atrophy at baseline and were found to be exposed to hidden gluten contamination while on a gluten-free diet, did not receive the additional gluten challenge.
"While the primary endpoint in the study, the effect on Villous Height to Crypt Depth ratio (VH:CD) was not statistically significant, AMG 714 ameliorated gluten-triggered effects across a range of endpoints," Dr. Leon and colleagues report in their meeting abstract.
For patients taking 300-mg AMG 714, "meaningful differences" (P=0.02) were observed in the Celiac Disease Patient-Reported Outcome, they note. Protection against gluten-triggered symptoms was seen in the Bristol Stool Form Scale (BSFS) scores as well, with patients in the placebo group experiencing an increase in diarrhea, which was not seen in the patients taking 150 mg (P=0.01) and 300 mg (P<0.01) of AMG 714, the researchers report.
At week 12, despite high-dose gluten challenge, none of the patients who took the 300-mg dose was judged by the lead investigator to have active disease compared with 33% of the patients in the placebo group. No symptoms associated with accidental gluten consumption were seen in the subgroup that did not receive the gluten challenge.
There were no serious adverse events or safety signals in the study. The most common adverse events related to AMG 714 included injection site reactions and pain, headache and upper respiratory tract infection.
"It's important to note that AMG 714 is intended to protect against modest contamination of gluten and not against the effects of deliberately eating large amounts of gluten, like bread or pasta," Dr. Leon told the briefing. "But we know that people with celiac disease are inadvertently exposed to gluten and it is our hope that AMG 714 will allow these patients to experience fewer gluten-triggered events."
The study was funded by Celimmune, which was acquired by Amgen in 2017 after study completion. Dr. Leon is a consultant for Amgen.
SOURCE: https://bit.ly/2sbu9Ra
Digestive Disease Week (DDW) 2018.0 -
COMMENTARY
Diet and a New Drug: A One-Two Punch Against Gluten?
Digestive Disease Week (DDW) 2018
William F. Balistreri, MD
DISCLOSURES
Director Emeritus, Pediatric Liver Care Center; Medical Director Emeritus, Liver Transplantation, Cincinnati Children's Hospital, Cincinnati, Ohio
Disclosure: William F. Balistreri, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Otsuka Pharmaceutical Co., Ltd
Received research grant from: Gilead Sciences, Inc.
August 01, 2018
"The Real Challenge: Avoiding Gluten
Studies presented at this year's Digestive Disease Week addressed an ongoing challenge for patients with celiac disease (CD): adherence to a gluten-free diet.
Once a diagnosis of CD has been confirmed, strict avoidance of exposure to gluten is recommended. However, the challenge of adhering to a gluten-free diet is exacerbated by the fact that variable amounts of gluten contaminate "gluten-free foods" because of less than precise food production, processing, packaging, or preparation. In addition, labeling may be inexact. Inadvertent exposure to gluten also may be associated with exposure to nonfoodstuffs (eg, lipstick, toothpaste). As a result of contamination, patients may continue to have mucosal inflammation despite a gluten-free diet.
Whereas the amount of gluten is known for individual products, the degree of inadvertent exposure to gluten by persons with CD is unknown. Gluten immunogenic peptide (GIP) analysis, which allows direct and quantitative assessment of gluten exposure, has been shown to be of value in the diagnosis and clinical management of patients with nonresponsive or refractory CD.[1]
Silvester and colleagues[2] determined the amount of gluten ingested by highly motivated, educated patients with CD adhering to a gluten-free diet by measuring the levels of GIPs in food, urine, and stool and the relationship with gluten exposure and persistent villous atrophy or related symptoms. As part of the study, participants also saved "doggie bags" for analysis that contained a sample of any processed or cooked food consumed.
Gluten was detected in at least one sample from 86% of patients consuming a gluten-free diet. Overall, approximately 33% of food samples positive for GIPs contained > 20 ppm of GIPs, with some containing > 100 ppm of GIPs. The estimated amount of GIPs ingested ranged from 0.23 mg to > 40 mg per exposure.
These novel data confirm that strict gluten avoidance is difficult to achieve, even by those who are highly motivated and educated.
AMG 714
Because it is difficult for a patient with CD to completely avoid gluten exposure, another level of protection—beyond a gluten-free diet—is needed.
Two studies presented an alternative strategy: the use of an experimental biologic drug to reduce symptoms and inflammation after gluten exposure. This new agent, AMG 714, is an investigational monoclonal antibody that blocks the effect of interleukin 15 (IL-15), a known intestinal inflammatory mediator in patients with CD.
In a randomized, double-blind, placebo-controlled phase 2a study, patients received six subcutaneous doses of AMG 714 (150 mg or 300 mg) or matching placebo over a 10-week period.[3] From weeks 2 to 12, selected patients received a high-dose gluten challenge (approximately 2.5 g/day for 10 weeks). The primary endpoint, the effect on the villus height to crypt depth ratio, was not statistically significant, but AMG 714 reduced gluten-triggered effects across several endpoints. Among the gluten challenge group, the 300-mg dose significantly improved patient reported outcome scores, and both doses reduced the number of weeks with diarrhea.
This agent may also be useful for refractory celiac disease type II, also called "pre-enteropathy-associated T-cell lymphoma" (pre-EATL), which arises as a complication of CD. This condition is a devastating and rare small bowel in situ lymphoma. The prognosis is poor; 50% of patients progress to EATL, and 5-year survival is about 45%.[4]
The presence of pre-EATL is defined by an aberrant monoclonal intraepithelial lymphocyte (IEL) population. IL-15 plays a major role in pre-EATL; it exerts antiapoptotic effects on aberrant IELs and is the key driver for transformation of IELs during lymphoma development. AMG 714 (anti–IL-15) prevents signaling of the IL-15 receptor complex on the cell surface of the IELs and halts proliferation and activation.
In a randomized, double-blind, placebo-controlled phase 2a study conducted by Cellier and colleagues,[4] patients received seven doses of AMG 714 (8 mg/kg) or matching placebo over 10 weeks. The primary endpoint, reduction in aberrant intestinal IELs, was not statistically significant between the groups. However, AMG 714 was associated with interruption in the progression of the disease. In addition, a numeric reduction occurred in the percentage of small-bowel aberrant IELs (2.5% increase from baseline) compared with placebo (7.3% increase from baseline). There was a 27% improvement in villous atrophy versus no improvement in placebo recipients.
In both studies, there were no serious adverse events or safety signals associated with AMG 714. Immunogenicity was low, and neutralizing antibodies were not detected.
These proof-of-concept and proof-of-mechanism studies indicate that AMG 714 (anti–IL-15) is effective in ameliorating the effects of gluten in patients with CD. Therefore, AMG 714 merits development as an adjunct to a gluten-free diet, offering a potential medical approach to alleviating symptoms for patients inadvertently exposed to gluten. However, the investigators caution that this approach is intended to protect against modest gluten contamination; it is not designed to counteract the effects of regularly eaten large amounts of gluten."
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bump to page one to help newbies!
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Finally another 'quickie article' on CD from Medscape this morning in my in-box.
Lactobacilli Reduce Wheat-Induced Intestinal Inflammation in Mice
March 04, 2019NEW YORK (Reuters Health) - Lactobacilli reduce wheat-induced intestinal inflammation in mice by degrading wheat amylase trypsin inhibitors (ATI), researchers report.
Gluten has been suggested to trigger inflammation and gastrointestinal symptoms. Among the non-gluten proteins in wheat, ATI have been shown to induce an innate immune response, but their role in gluten/wheat-related disorders has not been fully explored.
Dr. Elena F. Verdu from McMaster University, in Hamilton, Canada, and colleagues investigated the relative contributions of ATI and gluten in the induction of gut dysfunction in mice and evaluated the impact of lactobacilli on the inflammatory effects of ATI.
In these mice, ATI induced gut barrier dysfunction and exacerbated gluten-induced immunopathology, the team reports in Gastroenterology, online February 22.
ATI upregulated the expression of several pro-inflammatory genes relevant to celiac disease pathogenesis. And intestinal microbiota analyses revealed suppression of Lactobacillus and the Firmicutes/Bacteroidetes ratio in response to dietary administration of ATI.
However, Lactobacilli derived from the human gut and found to have high ATI-degrading capacity ameliorated many aspects of gut dysfunction induced in mice by wheat immunogenic proteins.
"The results show complex interactions between immunogenic proteins, host receptor pathways, and genetic factors that may inform the highly controversial clinical discussion regarding the etiology of functional alterations induced by wheat-containing diets," the researchers conclude. "Microbiome-modulating strategies based on the use of strains with specific ATI-degrading capacity could be developed and tested in clinical trials to support, or replace dietary restrictions, in patients with wheat-sensitive disorders."
Dr. Verdu did not respond to a request for comments.
https://ncbi.nlm.nih.gov/pubmed/26456581
You can request full transcript here: "researchgate"0 -
Please keep posting these articles. Really appreciate the info.0
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New Gastroenterology article in Medscape Apr 22/2019
The Overlap of Irritable Bowel Syndrome and Noncoeliac Gluten Sensitivity
Anupam Rej; David S. Sanders
Curr Opin Gastroenterol. 2019;35(3):199-205.
DISCLOSURES:
Anupam Reja - a, and David S. Sanders - a,b
a-Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust and b-Academic Unit of Gastroenterology, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
There are no conflicts of interest.Abstract and Introduction
Abstract
Purpose of review: There has been significant interest in gluten over the last decade, with an increase in interest of gluten-related disorders outside coeliac disease. Particularly, there has been a focus on the role of gluten in noncoeliac gluten sensitivity (NCGS) and irritable bowel syndrome (IBS). There is significant overlap between both of these conditions, with the aim of this review to explore their complex relationship.
Recent findings: Gluten has been demonstrated to generate symptoms in individuals with NCGS. However, there appears to be an increasing role for gluten in symptom generation in patients with IBS also. Other components of wheat, other than gluten, are now also thought to be contributing factors in symptom generation.
Summary: There appears to be significant overlap between IBS and NCGS. It is likely that a subset of patients presenting with IBS actually have NCGS. In addition, it is likely that individuals with IBS may also have symptoms triggered by gluten. With the pathophysiology of both conditions not fully understood, as well as increasing knowledge of wheat components in symptom generation, further research is required to help distinguish between both.
Introduction
There has been a significant increase in the interest in gluten over the last decade, with over $15 billion spent in the gluten-free industry in the United States alone in 2016.[1] Many individuals report wheat sensitivity, having been reported as 10%.[2] However, only 1% of individuals have coeliac disease.[3] This has led to an interest in gluten-related disorders outside the diagnosis of coeliac disease, with a recent focus on noncoeliac gluten sensitivity (NCGS) and irritable bowel syndrome (IBS).
NCGS is a condition first described in the late 1970s.[4] It is characterized by the development of intestinal and extraintestinal symptoms following the ingestion of gluten, provided that coeliac disease and IgE-mediated wheat allergy have been excluded. IBS presents with symptoms similar to NCGS, including abdominal pain, bloating and change in bowel habit.[5]
Whilst gluten has been noted to trigger symptoms in individuals with IBS and NCGS, it is now understood that other components in wheat may also trigger symptoms. These include amylase trypsin inhibitors (ATIs), wheat germ agglutenins (WGAs) and fermentable oligosaccharides, disaccharides , monosaccharides and polyols (FODMAPs).[6] With a lack of biomarkers for NCGS and a similar presentation to IBS, this has made it challenging to distinguish between these two clinical entities. This aim of this review is to explore the overlap between both of these conditions.
Whilst the pathophysiology of NCGS is not fully understood, it has been hypothesized that individuals with NCGS may have non-IgE-mediated wheat allergy.[18] In a large study by Carroccio et al.,[16] it was noted that the majority of individuals with wheat sensitivity were demonstrated to be suffering from cow's milk protein sensitivity. This condition is well known in the paediatric population, and could potentially suggest a non-IgE-mediated food hypersensitivity.[18] Also, a higher frequency of food allergy in the paediatric age was noted in the study, which would support this hypothesis.[18]
Elevated levels of fatty acid-binding 2 protein, a marker of intestinal epithelial cell damage, have been demonstrated to be elevated in patients with NCGS, also supporting the hypothesis of compromised intestinal epithelial barrier integrity.[20]
Gluten has been demonstrated to effect bowel barrier function in patients with IBS. A randomized controlled trial (RCT)[23] in 45 patients with IBS-D involved a 4-week trial of either a gluten-free diet (GFD) or gluten-containing diet (GCD). Small bowel permeability was demonstrated to be higher on a GCD, which was greater in HLA-DQ2/8-positive than HLA-DQ2/8-negative patients. Expression of tight junction proteins (ZO-1, occludin and claudin-1) were demonstrated to be lower on a GCD. Another study[24] also demonstrated changes in tight junction proteins following gluten in IBS. This study demonstrated alterations in myosin light chain phosphorylation and claudin-15 and claudin-2 expression with gluten. These findings could potentially explain the changes in intestinal permeability seen in patients with IBS following gluten challenge.[24]
Interestingly, in 36 patients with IBS and suspected food intolerance, confocal laser endomicroscopy (CLE) has shown immediate and dramatic mucosal responses to several antigens. Mucosal responses to antigens were seen in 22 of the 36 patients, including wheat (n = 13). Intraepithelial lymphocytes increased, epithelial leaks/gaps formed and intervillous spaces widened in individuals who had mucosal responses to antigens.[25] This interesting method may help to identify individuals with IBS who have food sensitivity.
Wheat Components Other Than Gluten
The wheat grain has been demonstrated by proteomic analysis to contain several individual components. Wheat grains constitute about 10–12% of protein, of which 80% is gluten.[26] Whilst there has been a focus on gluten leading to the induction of symptoms in NCGS and IBS, several other components of wheat have been implicated as a causal factor, including amylase/trypsin inhibitors (ATIs), wheat germ agglutinins (WGAs) and fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs).[6]
Wheat ATIs represent a family of up to 17 proteins[27] and represent around 4% of the total wheat proteins.[28] ATIs are associated with baker's asthma,[29] and have been suggested as an aetiological mechanism in NCGS by activation of the innate immune system. Wheat ATIs have been demonstrated to drive intestinal inflammation via the activation of toll-like receptor 4, in vitro and in vivo.[30] The activation of toll-like receptor 4 is thought to lead to the upregulation of maturation markers and release of pro-inflammatory cytokines, leading to an innate immune response.[27] It is also thought that modern hexaploid wheat contains higher ATI activity than older variants.[27]
Lectins are generally regarded as antinutrients within food, with WGA being the best studied serial grain lectin. WGAs have been demonstrated to induce an inflammatory response by immune cells.[31] They have been demonstrated to affect enterocyte permeability, which could lead to the translocation of microbial and dietary antigens interacting with the cells of the immune system.[31] It is important to note, however, that human data demonstrating the effect of WGA on inflammatory markers is lacking.[31]
Fructans, which are part of the FODMAP family, are the major short-chain carbohydrates present in wheat-based grains. FODMAPs may lead to the initiation of symptoms in patients with NCGS and IBS. They are short-chain carbohydrates, which are poorly absorbed, leading to an increase in small bowel water content and intestinal transit.[32] They are subsequently fermented in the large bowel, leading to intestinal gas production and distension, which may lead to symptom generation in individuals.[33] Interestingly, similar physiological responses have been noted in healthy individuals as well as those with IBS.
Whilst the Salerno experts' criteria have enabled NCGS to be formally diagnosed, this may not be practical to implement in clinical practice. Many individuals who note that gluten causes symptoms are unlikely to undergo a gluten challenge. Also, issues remain with diagnosis, as several different study designs are used, as well as individuals having an anticipatory nocebo response, which may affect the reported prevalence. Further research is required to understand the pathophysiological basis of NCGS and identification of biomarkers to help aid diagnosis and distinguish between IBS.
There is now emerging evidence that individuals with IBS also may have sensitivity to gluten, with evidence to support a GFD in these patients. A RCT in 45 patients with IBS-D,[23] where patients were placed on a 4-week GFD or GCD, demonstrated an increased number of bowel movements per day on a GCD versus GFD (P = 0.04). A prospective study in 41 patients with IBS-D,[39] evaluating a 6-week GFD demonstrated a reduction in IBS Symptom Severity Score (IBS-SSS) from 286 to 131 on a GFD (P < 0.001). There have been several trials evaluating gluten in IBS and NCGS, as seen in Table 1.
A double-blind crossover trial in 59 individuals with self-reported NCGS,[40] noted a significant increase in gastrointestinal symptom rating scale (GSRS) score in those consuming fructans versus gluten (P = 0.049). This may suggest that fructans is the causal agent for symptoms rather than gluten. However, it has also been highlighted in the literature[5] that FODMAPs as a whole are unlikely to be purely responsible for symptoms experienced by NCGS patients, as individuals improve on a GFD, despite receiving FODMAPs from other sources outside wheat, such as legumes. Also, extraintestinal manifestations of NCGS cannot be explained by the mechanism of action of FODMAPs.
Conclusion
There appears to be significant overlap between NCGS and IBS. It is likely that a subset of patients presenting with IBS symptoms actually have NCGS, best diagnosed currently using the Salerno experts' criteria, although not without its limitations. Whilst individuals with NCGS note that gluten induces symptoms in comparison to IBS, it appears that individuals with IBS may benefit from a GFD also. There is currently debate with regards to the component of wheat is responsible for symptom generation, with further research required to delineate the pathophysiology of both NCGS and IBS. The development of accurate biomarkers in the future may help delineate NCGS and IBS further.
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New Medscape email the other day.... very interesting if you have small children or are pregnant:
Early-Life Gluten Intake Linked to Increased Risk of Celiac Disease
By Will Boggs MD
June 24, 2019NEW YORK (Reuters Health) - Higher intake of gluten early in life is associated with an increased risk of celiac disease (CD) and CD autoimmunity, according to new findings.
"We found that 1-year-olds in the highest third of gluten intake had a two-fold increased relative risk of developing celiac disease autoimmunity (CDA), a potential prodromal stage of celiac disease," said Dr. Karl Marild from the Norwegian Institute of Public Health, in Oslo, Norway, and Queen Silvia Children's Hospital, in Gothenburg, Sweden.
"For me, it was a surprising to find this magnitude of association given the ubiquitous nature of gluten in our diet," he told Reuters Health by email.
Gluten intake drives the pathology associated with celiac disease, but it remains unclear whether the amount of gluten intake predicts later CD or CDA.
To investigate, Dr. Marild's team used data from 1,875 participants in the prospective Diabetes Autoimmunity Study in the Young (DAISY). Compared with 1-year-olds in the lowest third of gluten intake, those in the highest third had a 96% increased risk of CD (P=0.09) and a significant 2.17-fold increased risk of CDA.
The association between gluten intake in 1-year-olds and future CDA and CD did not differ by the child's HLA genotype or family history of CD, the researchers report in The American Journal of Gastroenterology, online May 9.
The incidence of CD increased with the cumulative gluten intake throughout childhood (corresponding to a 15% increase in risk per standard deviation of cumulative gluten intake by age 6, P=0.04), whereas the cumulative gluten intake throughout childhood was not associated with CDA risk.
"While the strength of association was similar for the outcome celiac disease and celiac disease autoimmunity, only the latter reached statistical significance (possibly related to the fact that this outcome was more prevalent)," Dr. Marild said. "However, if our findings are corroborated, they may provide a somewhat better understanding on one significant aspect of the likely multifactorial etiology of this disease."
"It is important to stress that we do not recommend a change in pediatric feeding practices," he said. "Because this is an observational study, there are many possible explanations to our findings, including non-causal explanations related to bias."
"Our conclusions are subject to the caveat that this study was restricted to genetically at-risk children from Denver, U.S.," Dr. Marild cautioned. "We do not know the extent to which these results can be generalized to other populations. Previous data in this field of research are relatively scarce and have yielded inconsistent results."
SOURCE: https://bit.ly/2x5ICRo
Am J Gastroenterol 2019.0 -
June 27/2019 Medscape article:News > Reuters Health Information
Vitamin Deficiencies May Be the Only Sign of Celiac Disease
By Linda Carroll
June 26, 2019
(Reuters Health) - Adults with undiagnosed celiac disease often have nutrient deficiencies as the only sign of the condition, researchers say.
Doctors often look for typical signs like unexplained weight loss or extreme thinness, but the hallmark signal of celiac disease may be low levels of vitamins and other micronutrients, they report in Mayo Clinic Proceedings, June 24.
"People have preconceived ideas of what celiac disease looks like," said study coauthor Dr. Joseph Murray, a professor of medicine at the Mayo Clinic in Rochester, Minnesota. "They expect to see patients who because of nutrient malabsorption and diarrhea will end up being skinny with lots of deficiencies. But now we have lots of patients who haven't lost weight - and many who are quite overweight - but still have micronutrient deficiencies. While they are not losing calories, they are not absorbing some vital nutrients."
Practically speaking, that means doctors need to be on the lookout for low levels of certain micronutrients, in particular iron, vitamin D and zinc, Murray said. Since many patients aren't getting regular blood tests, they may need to be attuned to the telltale symptom of iron deficiency: fatigue, he added.
"It's a very common symptom," Murray said. "People come in and say they don't have the energy they used to, whether it's during exercise or doing daily living activities. This illustrates they might be deficient in iron because of hidden celiac disease. They don't have diarrhea or belly pain, but they have no iron because of damaged intestines. And while a patient taking large quantities of iron might absorb enough to correct anemia, it's not going to fix the inflammation in the intestines and it's not going to prevent other complications that can occur later in life."
The initial screen for celiac is a blood test, Murray said. "If that comes back positive then the patient needs to be referred to a gastrointestinal specialist since you want to make sure it's really celiac before coming to a lifelong diagnosis that will require lifelong treatment."
Murray suspects that as many as 50 percent of adults with celiac disease go undiagnosed either because they don't have weight loss and other signs and symptoms thought to be typical of the disease or because they've put themselves on a gluten-free diet, which can skew the results of the blood test.
Murray and his colleagues studied 309 adults newly diagnosed with celiac disease between 2000 and 2014. The patients were matched by age with participants from the National Health and Nutrition Examination Survey (NHANES), a nationally representative database.
When the researchers compared the just-diagnosed celiac patients to NHANES participants, they found some big differences in nutrient levels. Zinc was deficient in 59.4% of those with celiac versus 33.2% of controls; copper was low in 6.4% of celiac patients versus 2.1% of controls, folate was low in 3.6% of celiac patients versus 0.3% of controls and vitamin B12 was low in 5.3% of celiac patients versus 1.8% of controls.
Among celiac patients, iron was low in 30.8%, but there were no controls with iron measurements to compare to. And contrary to traditional assumptions about celiac and thinness, weight loss was seen in just 25.2% of patients diagnosed with the disease.
Murray hopes the new study will serve as a heads-up to primary care physicians who might notice nutrient deficiencies in their patients. He cautions them to remember "just because someone is overweight doesn't mean they don't have celiac disease."
Unfortunately, doctors tend to get caught up treating symptoms rather than looking for an underlying cause, said Dr. David Whitcomb, a professor in the division of gastroenterology, hepatology and nutrition at the University of Pittsburgh. While nutritional deficiencies are common in the general public, they are more common among those with celiac disease, Whitcomb said.
"The message is that if you see nutritional deficiencies you should start thinking about celiac disease," Whitcomb said. "That way you may save these patients from damage to the intestines."
SOURCE: http://bit.ly/2XCi8Wq
Mayo Clin Proc 2019.0 -
Hi all, finally a new update and article from Medscape on Celiac Disease July 29/2020.
Tofacitinib Triggers Celiac Disease Remission in a Gluten-Eating Patient
SOURCE: https://bit.ly/2CRJxeM Annals of Internal Medicine, online July 27, 2020.NEW YORK (Reuters Health) - A patient who started tofacitinib therapy for alopecia areata had complete histologic and serologic remission of his celiac disease (CD), despite being on a gluten-containing diet, according to a new case report.
"This is a very interesting finding, but it's only one patient, one case," Dr. Lucas Wauters of University Hospitals Leuven in Belgium told Reuters Health by phone. He and his colleagues are awaiting the findings of a trial of tofacitinib as salvage therapy for patients with refractory CD type II, now underway at VU Medical Center, to move forward with additional studies.
In the current report, published in the Annals of Internal Medicine, a patient diagnosed with CD at age 1 year and alopecia areata at age 13 stopped his gluten-free diet at age 16 after going into remission. The re-introduction of gluten led to a relapse of severe small intestinal damage, but the patient reported no intestinal or extraintestinal symptoms.
He decided to continue on a gluten-containing diet, and the histologic and serologic abnormalities were still present in 2018. The following year, he began taking 5 mg of tofacitinib twice daily for alopecia. In 2020, follow-up studies showed full histologic and serologic remission of CD.
The patient continued taking tofactinib with regular blood tests to monitor blood count, lipid levels and creatine kinase.
"The efficacy of tofacitinib in alopecia areata may also be related to inhibition of CD8+ T-cell reactions to follicle-associated autoantigens," Dr. Wauters and his team write.
If the findings are confirmed, the researcher noted, the advantages of tofacitinib for patients with refractory CD could outweigh the potential risks. While the patient in the case report was on the maximum therapeutic dose of tofacitinib, he added, lower doses with a better safety profile may also be effective, and could be tested in patients with CD who have unintentional gluten exposure.
"It's interesting to use one drug which would target both diseases," Dr. Wauters added, noting that there are drugs now available that treat both psoriatic arthritis and inflammatory bowel disease.0 -
New info from Medscape (Aug 31/2020)
Immune Response Distinguishes Celiac Disease From Gluten SensitivityNEW YORK (Reuters Health) - The IgG antibody response to gluten is different in people with celiac disease and non-celiac gluten sensitivity, respectively, researchers report.
"What's exciting about these results is that for the first time they demonstrate a clear difference in the immune response to gluten between patients with celiac disease and patients with wheat sensitivity in the absence of celiac disease, which is commonly referred to as non-celiac gluten or wheat sensitivity (NCGS)," Dr. Armin Alaedini of Columbia University Medical Center, in New York City, told Reuters Health by email.
IgG antibody to gluten increases to similar levels in patients with celiac disease and NCGS, but whether B cells react differently to gluten in these conditions has been unclear.
Dr. Alaedini and colleagues evaluated the IgG subclass distribution in celiac disease and NCGS and its relationship to intestinal cell damage in their study of 40 patients with biopsy-proven celiac disease, 80 individuals with NCGS, 40 healthy volunteers, 49 patients with irritable-bowel syndrome, and 63 patients with functional dyspepsia.
Among patients with celiac disease, the anti-gliadin IgG response was comprised mainly of IgG1 and IgG3, whose levels were significantly increased in comparison with the NCGS group and healthy controls. IgG2 was also increased compared with the healthy group.
In contrast, the NCGS group had significantly elevated IgG4 (compared with the celiac disease and healthy groups) and IgG2 (compared with the healthy group), the researchers report in Gastroenterology.
There was no significant association between any anti-gliadin IgG subclass and the Marsh type, HLA-DQ2/DQ8 status, or fulfillment of diagnostic criteria for irritable-bowel syndrome or functional dyspepsia.
Serum concentrations of intestinal fatty acid-binding protein (FABP2), a specific marker of intestinal epithelial-cell damage, were elevated to a similar extent in the celiac disease and NCGS groups, compared with the healthy group.
Within the celiac disease group, anti-gliadin IgG3 correlated with FABP2, whereas FABP2 levels in the NCGS group correlated with anti-gliadin IgG4 and weakly with IgG1.
"As a disease progresses (such as in an infection or an allergy), the IgG antibody subclass distribution may evolve to take on a more or less inflammatory character." Dr. Alaedini explained. "The data in our study show that celiac disease and NCGS are quite different in the subclass distribution of IgG response to gluten, as well as in the relationship between these subclasses and the presumed intestinal pathology. This contrast is likely reflective of differences in the progression and disease relevance of B-cell immune responses in celiac disease versus NCGS."
"The prominence of the IgG3 subclass and its close relationship with the autoimmune response and intestinal cell turnover in celiac disease is suggestive of repeated activation of gluten-specific naive B cells," he said. "This is in spite of the chronic nature of celiac disease, which one might expect to lead to activation of memory cells in response to gluten exposure and an eventual subclass switch to the less inflammatory IgG2 and IgG4. If immune cells (including T cells and B cells) can be driven towards more tolerogenic and less inflammatory phenotypes, we may be able to prevent or reduce the severity of the adverse immune reaction to gluten in patients."
"I hope these data help in increasing awareness among physicians that sensitivity to wheat in the absence of celiac disease is a distinct condition with a biological basis," Dr. Alaedini said. "While a complex clinical work up is currently needed to evaluate patients, we will likely have established biomarkers in the future to help physicians in diagnosing patients more easily and accurately."
"The information we are learning about NCGS and celiac disease through studying these conditions together can also provide important insights for developing effective treatments beyond dietary restriction," he said.
bolding = my emphasis
SOURCE: https://bit.ly/3giCs5g Gastroenterology, online July 20, 2020.
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Hi everyone: New in my Medscape mailbox April 12/2021
The IgA tTG for Celiac Disease: Not as Sensitive as We Thought?
Jim Kling
April 12, 2021Immunoglobulin A tissue transglutaminase offers a noninvasive way to detect celiac disease, but new research suggests that its sensitivity may be overestimated and that it may not be an effective screening test, at least in asymptomatic individuals. The reason comes down to verification bias, wherein a technique appears to have higher sensitivity and lower specificity because individuals who screen positive are more likely to have their disease confirmed by a follow-up small-bowel biopsy while those who screen negative are unlikely to have a follow-up biopsy that could reveal missed celiac disease.
"The issue with verification bias is that only the patients that screen positive on that index test are going to be getting the reference test, so there's probably a good chance that if they screen positive when they go to that reference test they'll also be positive. What you're missing from when you're calculating sensitivity is, what about the ones that are negative on the index test? Would they have been positive on that reference test? That's not even coming into your calculation because they're not getting that reference test," said Marisa Stahl, MD, a physician and researcher at the Children's Hospital Colorado Center of Celiac Disease in Aurora. Stahl was not involved in the meta-analysis, but commented on it in an interview.
The only way to fully correct for this bias is to conduct both IgA tissue transglutaminase (tTG) testing and small bowel biopsy on a complete or random sample of patients and compare the sensitivity and specificity of IgA tTG with the preferred method small-bowel biopsy. However, this is rarely done. Instead, when the U.S. Preventive Services Task Force concluded that evidence was insufficient for IgA tTG testing for celiac disease, it relied on a 2016 comparative effectiveness review of nine studies that estimated sensitivity at 92.6% and specificity at 97.6%. USPSTF remained noncommittal because of inadequate evidence surrounding the balance of benefit and harms of screening for celiac disease in asymptomatic individuals.
In the current meta-analysis, Isabel Hujoel, MD, of the Mayo Clinic, Rochester, Minn., and colleagues tested whether the studies used by USPSTF may have overestimated sensitivity because of verification bias. In a report in the Journal of Clinical Gastroenterology, they reviewed those same nine studies to see the potential impact of verification bias. They rated each individual study as being at high, low, or unclear risk of verification bias and found five they considered to be high risk.
To reveal the impact of small-bowel biopsy referral rates on sensitivity and specificity, the researchers reviewed a separate set of nine retrospective and prospective studies to determine the frequency of referral for both IgA tTG–positive patients (positive referral rate) and IgA tTG–negative patients (negative referral rate), which were 79.2% and 3.6%, respectively.
The researchers then used these values to recalculate the sensitivities and specificities in the five original studies considered high risk for verification bias, then pooled those adjusted values with the remaining, unadjusted values from the studies considered low or unclear risk of bias. The new overall values were 57.1% sensitivity (95% confidence interval, 35.4%-76.4%) and 99.6% specificity (95% CI, 98.4%-99.9%).
"The reported sensitivity and specificity of IgA tTG ... are substantially biased due to a lack of adjustment for verification bias. Specifically, adjusting for verification bias decreases the sensitivity of IgA tTG from 92.5% to 57.1%, with a drop in the lower limit of the 95% CI to 35.4%, and an increase in the specificity from 97.9% to 99.6%, The low estimated sensitivity of IgA tTG raises concern on the accuracy of this test and supports performing a systematic review that accounts for verification bias. ... After adjusting for verification bias, the estimated sensitivity of IgA tTG falls to the point where the serologic marker may no longer be clinically useful as a screening test," the authors wrote.
The numbers came as a bit of a shock to Stahl because the sensitivity was so much lower than has been traditionally accepted. "But the more important concept from the paper is that the sensitivity is probably lower than what we oftentimes reference, and we should think more about the population of patients that could potentially screen negative and still have celiac disease," she said. Although there is no literature to back this up at this time, Stahl also believes that this may be more common in adults, who have a higher incidence of seronegative Celiac disease.
The issue isn't restricted to celiac disease. Verification bias can also affect the sensitivity and specificity values from other index screens that are followed by invasive reference tests, like occult blood and colonoscopy or hepatitis C serology and liver biopsy. "A lot of times you ethically cannot put everyone through the [more invasive] reference test, so it definitely applies to other tests we screen for in GI. When we're quoting numbers and doing systematic reviews and meta-analyses, we should be accounting for those biases," said Stahl.
No source of funding was disclosed. The authors declared that they have nothing to disclose. Stahl consults for Evo-Endo.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.0 -
Just an update to the thread....no new info re: Celiac or Gluten Intolerance in my Medscape inbox....Covid is still top of the lists for studies and new info right now.
Carry on, GF'ers!
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