In this Swedish cross-sectional cohort study with 162 children who had been diagnosed with celiac disease (CD) between 2013-2018, the authors examined the outcomes of children who had continued follow-up compared to those who had not been seen in 24 months. The average disease duration of study participants was 5.3 years.
Key findings:
Similar rates of TTG IgA normalization: 94% vs 91% for those without and those with follow-up respectively
Similar rates of very good dietary adherence 65% vs 72% for those without and those with follow-up respectively
Lack of follow-up was not significantly associated with growth, symptom scores, or HRQoL.
It is possible that there is a selection bias in that patients without symptoms may be less likely to followup.
My take: Based on this study, it looks like good education after diagnosis is crucial and that regular follow-up is less important in achieving good outcomes.
In 2022, a study in JPGN showed that the rate of Hepatitis B virus (HBV) vaccination and immunity was similar in individuals with and without celiac disease (CD). In addition, there was no increased risk of HBV infection detected in CD patients. Thus, routinely checking hepatitis B status in all patients with CD was no longer justified. (See: Celiac Disease, Hepatitis B and Paul Harvey).
The same researchers in this study expand their findings to inflammatory bowel disease (IBD) and CD. In this retrospective cohort (2000-2019), using the Rochester Epidemiology Project which includes data from 162,847 residents. Key findings:
1264 incident cases of IBD/CD, only 6 HBV infections were diagnosed before the index date; 5 of the 6 had risk factors including IV drug use or living in endemic region.
No new HBV infection developed in any of 1258 patients with IBD/CD during a median follow-up of 9.4 years
The proportion of patients with HBV-protective titers (≥10 mIU/mL) decreased with time before plateauing, with protective titer rates of 45% at 5 up to 10 years and 41% at 15 up to 20 years after the last HBV vaccination. The control population with protective titers also decreased similarly with time though was consistently higher than the levels of patients with IBD/CD within 15 years after the last HBV vaccination
Context/Discussion:
Only 16% of vaccine recipients have measurable protective titers by age 18 years, according to the CDC.32
“Time-related waning of Ab levels to HBV after vaccination has unclear clinical significance. Although screening persons for HBV immunity by using anti-HBs titers is widely accepted, prior study results have shown that cellular immunity can also provide long-term HBV protection, even in the setting of nonprotective titers.”
Reactivation of HBV is a well-documented complication of immunosuppression in patients with IBD, and screening for dormant infection is of paramount importance at diagnosis
Limitations: the study population had a low rate of HBV acquisition; thus, the study findings may not apply to areas with higher risk for HBV.
My take: This study shows that treating low hepatitis B surface antibody levels with reimmunization is likely NOT needed in either the IBD or the celiac disease population, except perhaps in those at high risk. Checking HBV status prior to immunosuppressive therapy, though, is still needed to prevent reactivation of HBV in those at risk.
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In this study, the authors analyzed laboratory testing results from pediatric patients newly diagnosed with celiac disease (2018-2021) to determine the usefulness of each test derived from recommended guidelines (J Snyder et al. Pediatrics 2016; 138: e20153147). Screening protocols in their center resulted in an estimated cost of approximately $320,000 during the study. Tests at diagnosis included hemoglobin, alanine/aspartate aminotransferase, ferritin, iron, TSH, Free T4, and vitamin D screening. These screening tests were done in ~80% of 468 patients.
Key findings:
Ferritin was abnormal in 29%, hemoglobin was abnormal in 12%, and iron was abnormal in 22%. Abnormal ferritin captured all patients in this cohort with an abnormal iron. If ferritin was used as an isolated screen with reflective iron testing, this would have reduced costs by about $12,000
AST and ALT were abnormal in 2% and 11% respectively
25-OH Vitamin D was abnormal in 14%. Recent data indicated that low Vit D levels are similar among patients with and without celiac disease (R Ahlawat et al. JPGN 2019; 69: 449-454)
TSH and Free T4 were abnormal in 7% and 0.3% respectively. For thyroid disease, TSH and free T4 testing did not lead to any new diagnosis of thyroid disease (7 carried a preexisting diagnosis). There were 19 additional patients with abnormal lab values who had more testing due to initial abnormalities. If TSH alone were used for screening, costs savings would be about $29,000. If no thyroid testing were done, this would have reduced costs by about $40,000.
Hepatitis B immunity was NOT present in 69%. However, recent studies have shown similar levels of immunity in those with and without celiac disease. In addition, it is not clear that a low level hepatitis B surface antibody always indicates a lack of immunity. Eliminating hepatitis B screening would have reduced costs by about $63,000.
The authors note that the cost savings by adopting their recommendations would have saved about $104,000 (out of $320,000).
My take: This is a very useful study and indicates that curtailing initial testing for celiac disease could reduce costs substantially and without compromising care. This would include notchecking a serum iron, a free T4, or hepatitis B studies. The authors note that the value of Vit D testing is also questionable but may be worthwhile due to increased risk of bone disease in individuals with celiac disease.
This retrospective study of patients with trisomy 21 (T21) who underwent EGD between 2000-2020. Key findings:
Among 836 patients with T21, 419 (50.1%) of whom had duodenal histologic abnormalities.
290 of 419 had villous atrophy (VA) and of those, 172 of 290 met celiac disease (CD) diagnostic criteria, while 118 of 290 did not meet CD criteria (nonspecific VA).
Only one of the 118 with nonspecific VA had markedly abnormal celiac serology (TTG IGA >10 times ULN) but had no IELs on biopsy and did not respond to GFD. Four patients with nonspecific VA were later diagnosed with celiac disease over a median of 2.5 years with conversion to abnormal celiac serology.
Among the 129 with duodenitis without villous atrophy, 38 (29%) had increased intraepithelial lymphocytes and two patients were diagnosed with CD many years later (development of VA and positive celiac serology.
The authors offer an algorithm (Figure 2) to assist clinical approach based on biopsy results in this population.
In those with no villous atrophy, if Marsh score of 0/1, biopsies not consistent with celiac disease. In those with Marsh score of 2 (which is rare), consider as consistent with celiac disease (see next bullet point).
In those with villous atrophy consistent with celiac disease, assess response to gluten free diet (GFD). In those without a response, consider RD consult to evaluate exposures and HLA-typing as next steps.
In those with villous atrophy NOT consistent with celiac disease, obtain serology (TTG IgA, EMA, IgA, DGP IgG). If serology is negative, consider peptic duodenitis or SIBO treatments and assess/discontinue medications for potential for mucosal damage. If serology is positive, consider HLA-typing, review pathology slides, assess for competing disorders, and could need f/u endoscopy.
My take: Overall, ~20% of patients with T21 undergoing endoscopy, will have pathology consistent with celiac disease; this represents ~40% of those with abnormal histology. In the other 60% with abnormal histology, many have alternative explanations for the histologic findings (like peptic duodenitis). Some will evolve to meeting the diagnostic criteria for CD with time indicating need for ongoing monitoring. This study highlights the diagnostic uncertainty in those with potential for seronegative celiac disease.
At the start of my training in pediatric gastroenterology, the serological testing was not reliable and as a result, very few cases of children who did not have a ‘classical’ phenotype (eg. abdominal distention, poor growth, anemia) were diagnosed. The main exception was the diagnosis in children already recognized as high risk (eg. children with type 1 diabetes).
This recent retrospective study indicates that even with improvement in celiac serology, there are cases of seronegative celiac disease (SN-CD) that are difficult to diagnose. In this study, SN-CD diagnosis required clinical correlation and either confirmatory genetics or follow up endoscopy on a gluten-free diet. Key findings:
Of the 424 patients who met celiac disease (CD) criteria, 4.7% (n = 20) fulfilled the criteria for SN-CD
Nearly 65% of SN-CD were IgA sufficient compared with 98.4% in the seropositive group
All SN-CD patients were symptomatic whereas 82% of seropositive group was symptomatic
The discussion notes that it has been understood that the sensitivity of TTG IgA is about 95% and specificity about 96%. However, the authors caution that this may be “largely overestimated due to failure to account for verification bias. Only 3.6% of IgA-ATTG negative individuals were referred for biopsy” in Hujoel et al meta-analysis (J Clin Gastroenterol 2021; 55: 327-334); thus, the sensitivity could be as low as 57% based on this meta-analysis. In addition, gluten restriction prior to serological testing can further reduce the sensitivity of serological tests.
An important limitation of the study is proving that SN-CD was in fact SN-CD and not one of the mimics for CD (eg. inflammatory bowel disease, autoimmune disorders, medication effect). However, they noted that their cohort had followup over 6-9 years and with symptom resolution with a gluten free diet.
My take: Identifying SN-CD is difficult since so many children have similar digestive symptoms unrelated to celiac disease. Most children with vague digestive complaints do not need to undergo endoscopy; as such, SN-CD can be easily overlooked.
Methods: A retrospective cohort study was performed using the Military Healthcare System database. N=968,524 children with 1704 cases of celiac disease (CD) in this group (from 2001 to 2013) with prescription for PPIs, H2RAs or antibiotics in first 6 months of life.
Key findings:
PPIs (HR, 2.23; 95% CI, 1.76-2.83), H2RAs (HR, 1.94; 95% CI, 1.67-2.26), and antibiotics (HR, 1.14; 95% CI, 1.02-1.28) were all associated with an increased hazard of CD.
The risk is increased by use of multiple categories of these medications and/or if acid suppression medications are used for longer periods
There have been previous studies indicating an increased risk of CD in patients given acid suppression (Lebwohl et al. Dig Liver Dis 2014; 46: 36-40) and conflicting data regarding the use of antibiotics. With regard to acid suppression, recent studies have indicated that these medications in infancy may increase the risk of food allergies as well. The authors speculate in their discussion that the increased risk for CD could be related to changes in protein degradation, mucosal permeability, microbiome changes, and immune reactivity. The authors note that their dataset did NOT show an increased risk of CD associated with C-section delivery.
One of the limitations of this study is that early presentations of CD could lead to prescriptions of agents to to help reduce symptoms rather than the medications increasing the risk of developing CD. However, this is unlikely as gluten introduction is often later in infancy.
My take: Better stewardship of antibiotics and acid blockers is needed. Use of acid suppression medications is associated with an increased risk of celiac disease as well as food allergies.
In this retrospective study, 49 patients were screened due to an affected first-degree relative with celiac disease. They were compared to 178 patients who were screened for other clinical indications. Key findings:
Although 51% of patients screened due to an affected first-degree relative were asymptomatic, their disease histology and TTG levels were as severe as those screened for symptoms suggestive of celiac disease (in the comparison group 16% were asymptomatic).
Comments:
“Previous studies have shown that asymptomatic adolescents and those diagnosed with CD by serologic screening are less likely to adhere strictly to a GFD when compared to younger children and adults diagnosed because of classical symptoms” (Dig Dis Sci. 2008 Jun; 53(6): 1573–1581).”
Some individuals who are thought to be asymptomatic, clinically improve with a gluten free diet (GFD). In one study, “the GFD group also had reduced indigestion (P=.006), reflux (P=.05), and anxiety (P=.025), and better health, based on the visual analog scale (P=.017), than the gluten-containing diet group” (Gastroenterology 2014 Sep;147(3):610-617).
My take: In this study, being asymptomatic (identified due to affected first-degree relative) was NOT associated with milder celiac disease based on serology or histology.
Background: Latiglutenase (IMGX003) is an investigational dual-enzyme drug candidate that acts to degrade gluten in vivo when consumed with a meal. The authors note that “despite strict adherence to a GFD, about half of CD patients show evidence of persistent small intestinal mucosal injury (Marsh grades II–III);’ thus, there is a need to improve treatment with other measures in addition to diet.
Methods: 43 patients (IMGX003, n = 21; placebo, n = 22) completed this double blind and placebo controlled study which assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease (CD) exposed to 2 g of gluten per day for 6 weeks study
Key findings:
In IMGX003-treated patients, there was less damage to mucosa. The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was –0.04 vs –0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018).
Measurements of gluten-immunogenic peptides (GIP) in urine indicated 95% gluten degradation in the stomach by latiglutenase.
The 2 g dose per meal of gluten allowed used in the study, “would likely substantially exceed that accidently occurring while on a GFD, 4 supporting such an approach for management for gluten-triggered symptoms in treated patients.”
Graphical abstract:
In both the placebo and IMGX003 groups, there was an increases in symptoms, but this was blunted in the treated group–Figure 2:
My take: This study shows the potential for latiglutenase to act as a ‘safety net’ to protect from CD from accidental gluten exposure. The findings reinforce the idea that this agent is not likely to be effective in the absence of gluten restriction. As an aside, I would be interested in finding out whether patients with presumed non-celiac gluten sensitivity would improve on this therapy.
Here are some of the recommendations from updated ACG Celiac Guidelines:
Comments: The authors favor a non-biopsy approach for Celiac diagnosis in children with very elevated serology but not in adults. In adults, they cite a paucity of literature. “One multicenter international study of adults found that a 10-fold elevation of TTG IgA had a positive predictive value of 95% for CD (50). Given the life-long treatment implications of a GFD, this may be unacceptably low.”
The authors suggest assessing for mucosal healing after 2 years of treatment in all patients though they indicate a low quality of evidence for this recommendation. In those undergoing endoscopy, biopsies of the duodenal bulb along with at least 4 post-bulbar biopsies are recommended.
Figure 3 provides an algorithm for non-responsive celiac disease.
Thank you to those who have helped me this past year with this blog –colleagues, friends and family. Wishing all of you a good 2023. Here are some of my favorite posts from this past year:
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