A long time ago I heard a joke from a mentor about how can you tell if a person is an optimist. An optimist is a person who finds a pile of manure under the tree on Christmas morning and declares: ‘Oh boy, I’m getting a pony.’
In this 6-week randomized, double-blind, placebo-controlled study with 159 participants, treatment with ZED1227, a selective oral transglutaminiase 2 inhibitor reduced histologic injury compared to placebo; all patients were receiving a diet with 3 grams of daily gluten. Key findings:
Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P=0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001)
The estimated differences from placebo in the change in intraepithelial lymphocyte density were −2.7 cells per 100 epithelial cells (95% CI, −7.6 to 2.2) in the 10-mg group, −4.2 cells per 100 epithelial cells (95% CI, −8.9 to 0.6) in the 50-mg group, and −9.6 cells per 100 epithelial cells (95% CI, −14.4 to −4.8) in the 100-mg group
Adverse events were similar to placebo; 3 (8%) patients in the 100 mg group developed a rash
The need for a treatment besides a gluten-free diet is significant; among adults, 40-50% do not achieve mucosal healing/recovery despite GFD institution; in addition, the diet is difficult and costly.
My take: I think it is still a long journey to find an effective & safe oral treatment for celiac disease.
Among 76 patients (median age 36.5 years) who were prospectively followed for 2 years, persistent villous atrophy was observed in 40 (53%). In this group, 72.5% were asymptomatic (based on Likert scales) and 75% had negative serology
Detectable fecal gluten immunogenic peptides (f-GIPs) were present in at least one sample in 69% of patients. (Two samples obtained at f/u visits which were ~every 6 months during study)
Excellent or good adherence to GFD was demonstrated in 68.4% of patients based on dietetic evaluations. Only 6 (8%) were clearly nonadherent
“There were no significant differences in the rate of clinical and serological remission between patients with villous atrophy and those with mucosal recovery”
The authors did not find potentially modifiable predictive factors
The authors note that serology is “not useful for monitoring patients on a GFD.” Anti-TTG2 and EMA, in a recent meta-analysis, had a pooled sensitivity of around 50%.
“Adults are significantly less likely than children to normalize their duodenal histology.”
The associated editorial by Rej et al (pg 946-948) outline a personalized approach for dealing with persistent villous atrophy:
In those with persistent symptoms/positive GIPs/elevated serology/micronutrient deficiency, the first step is careful dietetic assessment. After this, endoscopy could be considered to confirm presence or absence of mucosal healing.
In those with no symptoms and no abnormalities, use of monitoring endoscopy needs to be weighed against the costs as well as potential complications.
Other points in the editorial: 1. GIPs have poor concordance with mucosal healing and 2. causes of poor mucosal healing include the following: natural slow healing process, super sensitive to gluten, ongoing gluten exposure, and refractory celiac disease.
My take: This study shows that there is ongoing gluten exposure in the majority of patients even in those with excellent or good adherence to a GFD; in addition, it shows that clinical/serological markers are NOT effective in predicting mucosal healing in adults. Nevertheless, it is not clear that followup endoscopy is beneficial.
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This retrospective study provides insight into the predictive value of persistently abnormal celiac labs in symptomatic children.
Inclusion criteria: not eligible for a non-biopsy diagnosis AND children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies
Methods: Patients were classified in groups according to median TGA-IgA values: Group A (TGA-IgA>1 ≤ 5 × ULN; defined as “low-positive”), Group B (TGA-IgA > 5 < 10 × ULN; “moderate-positive”), and C (controls).
In group A, CD was diagnosed in 142/162 (87.7%)
In group B, all 62 children (100%) received a CD diagnosis
My take: In individuals with mild elevation of celiac serology, it is reasonable to recheck prior to confirming with endoscopy. However, those with persistently abnormal values are very likely to have celiac disease.
Two recent JPGN articles from the same researchers highlight changes in presentation and deficits of knowledge with celiac disease (CD). Interestingly, the authors chose to spell celiac disease differently in the two articles.
This retrospective study included data from 653 children and adolescents (median age 7 years 2 months; 63.9% girls) from Croatia, Germany, Hungary, Italy, and Slovenia were available for the analysis. Key findings:
One fifth (N = 134) of all children were asymptomatic.
In symptomatic children, the most common leading symptom was abdominal pain (33.3%), followed by growth retardation (13.7%) and diarrhoea (13.3%). Many children (47.6%; N = 247) were polysymptomatic.
Symptoms and signs of malabsorption (eg. diarrhea and distention) were significantly more common in younger (P < 0.001)
The investigators enrolled 53 adults with celiac disease (CD) for at least two years and followed symptoms as well as stool/urine testing for gluten immunogenic peptide (GIP). “GIP in stool can detect gluten consumption of more than 40 mg/d and the urine tests are positive from 40 and 500 mg/d of gluten.”
Over the 4-week study period, weekend samples (urine) identified 70% of patients excreted GIP at least once, compared with 62% during weekdays (stool).
Patients had a median of 3 exposures during the 4 weeks.
Also, the authors noted increases in GIP excretion towards the end of the study. “This suggests a potential Hawthorne effect that could be explained by a decrease in hypervigilance that often is seen in a context of research studies.”
The authors note that GIP “excretions of greater than 2 mcg/g in stool or greater than 12 ng/mL in urine can induce mucosal damage in almost 100% of patients.”
My take: This study adds to the body of literature emphasizing the high rate of inadvertent gluten exposure.
This study consisted of 14 adults with biopsy-proven celiac disease (CD) who were randomized to 3 g or 10 g gluten/day intake for 14 days. Each participant underwent extensive studies to detect histological, visible, and biochemical changes associated with gluten introduction. Data required multiple endosopic duodenal biopsies, VCEs and blood collection.
Symptoms and plasma interleukin-2 levels “increased significantly or near significantly at both doses.”
Interleukin-2 appeared to be the earliest, most sensitive marker of acute gluten exposure. IL-2 increases were observed 4 hours after exposure in patients with CD but not in healthy controls.
Intestinal damage is more complex and requires a longer duration and higher dose of gluten exposure. In this study, the higher dose (10 g) of gluten exposure was required for enteropathy within the study time frame.
My take: These study findings need to be confirmed in a broader patient cohort. However, in patients needing a gluten challenge, IL-2 response after a single-dose (measured at 4 hours) could be helpful. Those without IL-2 response are unlikely to have CD. Those with an IL-2 response at 4 hours, could confirm CD by completing a gluten challenge.
A recent large retrospective study (R Mandile et al. JPGN 2021; 72: 282-287. Seronegative Villous Atrophy in Children: Clinical and Immunohistochemical Features) provides information about conditions, besides celiac disease (CD) which present with villous atrophy. 64 of 1282 pediatric patients were seronegative with villous atrophy; seronegative was defined as testing negative twice for serology (TTG IgA/EMA or if IgA-deficient, IgG antibody serology).
Diagnoses were: inflammatory bowel diseases (IBD) (21/64), food allergy (8/64), infections (7/64, of which 3 HIV infections), immune deficiency (3/64), short bowel syndrome (3/64), congenital diarrhea (2/64), other/inconclusive diagnosis (8/64). In addition, there were 12 with Gastro-Esophageal Reflux Disease (GERD) & the authors speculate that perhaps hyperacidity could play a role in some of these cases.
Only one quarter of the seronegative patients had an increased number of intraepithelial lymphocytosis (IELs)
Among those with villous atrophy attributed to IBD, this was nearly equally-split between Crohn’s disease and ulcerative colitis, 10 and 11 patients respectively (according to Table 1)
The authors note that the ~5% of patients with seronegative villous atrophy with alternative diagnosis than Celiac disease may be an overestimation as more individuals are being diagnosed without biopsy based on serology
Despite the large cohort, there are still other rare conditions that were not identified in this study (eg. autoimmune enteropathy, CTLA4B deficiency,drug-induced enteropathy, and tropical sprue)
My take: This article provides a good starting point for patients with villous atrophy and negative serology.
The overall prevalence of celiac disease in the entire cohort was 0.6%. Of those with functional constipation, 1 (0.5%) was diagnosed with celiac disease, and 3 (0.7%) of the control patients
The authors note that some prior publications (references 11 and 12) have found a slight increase risk of celiac disease in children with constipation.
My take: In children with functional constipation, the yield from testing for celiac disease is very low and probably not significantly greater than the general population. In children with irritable bowel syndrome (which is often confused with constipation), the yield is probably a bit higher.
Beginning at 1 year after a diagnosis of CD, 29 patients (0.06%) received a diagnosis of small bowel adenocarcinoma vs 45 reference individuals (0.02%).
HRs were small bowel adenocarcinoma 3.05, carcinoids 0.59, and adenomas 5.73.).
Overall, there was 1 extra case of small bowel adenocarcinoma in every 2944 patients with CD followed for 10 years.
There was an inverse association between mucosal healing risk of future small bowel adenocarcinoma (HR, 0.18; 95% CI, 0.02–1.61), although the HR failed to attain statistical significance.
It is important to note that lymphoma is much more common malignancy than adenocarcinoma in celiacdisease. The authors, in their discussion, state: “compared with lymphomas, small bowel adenocarcinomas were approximately 10 times less common in patients with CD.” At the same time, with the discovery of milder cases of Celiac disease, lymphoma risk is not nearly as high as previously suggested. A large cohort study (Clinical Gastroenterology and Hepatology 2012; 10: 30-36) of ~45,000 did not see an increased risk of GI cancers beyond the first year after diagnosis. In addition, another study (Gastroenterology 2010; 139: 763), found that mortality NOT worsened in undiagnosed celiac disease (identified by review of serology) in Olmstead County, though bone density decreased. n=129 of 16,847. (?milder cases undiagnosed). Related post: Good News For Celiac Disease
My take (mostly borrowed from authors): There is a tiny increase in risk of “small bowel adenomas and adenocarcinomas in patients with diagnosed CD, but only a very marginal increase in terms of absolute risk. Our results do not imply a need for surveillance but celiac individuals with signs or symptoms of malignancy should merit further investigation for small bowel adenocarcinoma. Mucosal healing was strongly associated with lower risk of small bowel adenocarcinoma, although the association failed to reach statistical significance.’ Lymphoma is a more common malignancy associated with CD but the absolute risk remains low.