The Link Between Celiac Disease and Inflammatory Bowel Disease

IM Pinto-Sanchez et al. Gastroenterol 2020; 159: 884-903. Association Between Inflammatory Bowel Diseases and Celiac Disease: A Systematic Review and Meta-Analysis

Methods: The authors identified 65 relevant studies after searching databases including MEDLINE, EMBASE, CENTRAL, Web of Science, CINAHL, DARE, and SIGLE through June 25, 2019 for studies assessing the risk of CeD in patients with IBD, and IBD in patients with CeD

Key findings:

  • Among patients with celiac disease, there was an increased risk of IBD vs controls (RR 9.88; 95% CI 4.03–24.21); the risk was greater for Crohn’s disease than ulcerative colitis
  • Among patients with inflammatory bowel disease, there was an increased risk of celiac disease vs controls (risk ratio [RR] 3.96; 95% confidence interval [CI] 2.23–7.02); however, this finding needs to be interpreted with a lot more caution.
    • The population-based studies that identified this risk relied on ICD codes.
    • Celiac diagnosis is much more difficult in patients with IBD. Overdiagnosis is possible due to increased surveillance, and misinterpretation of serology (eg. false positive serology). In addition, the pooled prevalence in this study of 0.75%, while greater than the controls of 0.3%, remains lower that the current worldwide prevalence of approximately 1%.
    • Only more prospective cohort studies will prove a definitive increase in risk.

My take: In patients with either IBD or celiac disease, clinicians should consider additional diagnoses in patients with ongoing symptoms.

Gluten-Free Diet Can Be Unhealthy

In some patients with celiac disease, institution of a gluten-free diet may be detrimental without good dietary counseling as a highly-processed diet can increase the risk of adverse cardiovascular events.

A recent study (J Runde et al. JPGN 2020; 71: 533-535. A Narrow Window: Booming Gluten-free Market and Fostering Healthy Dietary Habits in Children With Celiac Disease) assessed dietary patterns of children with celiac disease and indicates that early counseling is crucial.

In total dietary surveys were completed for 100 children with celiac disease. Key findings:

  • 77% consumed processed gluten-free (GF) foods multiple times per day
  • 20% ate exclusively processed GF foods
  • The main reasons for processed GF foods were convenience and taste
  • Patients and families interest in dietary counseling diminished with time. In children <1 year from diagnosis, 35% were interested in dietary feedback, compared to 18% 2-3 years after diagnosis, 15% 4-6 years after diagnosis, and 11% at 7+ years from diagnosis

The authors speculate that highly-processed foods are leading to obesity which is increasingly reported in pediatric celiac disease.

My take:

  • The greatest opportunity for dietary counseling is at the time of the diagnosis.
  • Children with celiac disease commonly consume an unhealthy diet and are at risk for the same types of outcomes as children without celiac disease who also frequently consume an unhealthy diet

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It looks like the COVID-19 epidemic is going to get worse -while there is more testing, there is also a trend of more hospitalizations that is not likely explained by more testing.

Best Screening For Celiac At All Ages

Another study (MR Khan et al. J Pediatr 2020; 224: 158-61. The Utility of IgA-Based Serologic Markers in Diagnosing Celiac Disease in Children 24 Months of Age or Younger) shows that tissue transglutaminase (TTG) IgA is the best first test, even in children less than 2 years of age.

This was a multicenter retrospective study with 150 children, mean age was 18 months.

Key findings:

  • ~98% of children <2 years of age with celiac disease had an elevated TTG IgA
  • “These findings are consistent with recently published European guidelines, which endorse TTG IgA…as the initial screening test regardless of age.”
  • IgG-based test should be reserved for IgA-deficient children, which was noted in 5.5% of this cohort.
  • Endomysial antibody (EMA) had excellent specificity in this study but was less sensitive; it was negative in 13 of 66 (19.7%) of children with celiac disease (positive in 80%).

My take: TTG IgA is a good first step; based on clinical presentation, further testing (eg. endoscopy) could be warranted in highly-selected cases with negative results.

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Shared Genetic Risk of Celiac Disease, Crohn’s Disease, Ulcerative Colitis, and Collagenous Colitis

E Stahl et al. Gastroenterol 2020; DOI:https://doi.org/10.1053/j.gastro.2020.04.063 Link: Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases

“In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC.”

 

Why Celiac Serology Needs To Be Looked At Differently in Children with Type 1 Diabetes

A recent study (M Wessels et al. J Pediatr 2020; 223: 87-92Raising the Cut-Off Level of Anti-Tissue Transglutaminase Antibodies to Detect Celiac Disease Reduces the Number of Small Bowel Biopsies in Children with Type 1 Diabetes: A Retrospective Study) recommends changing the approach to celiac disease (CD) diagnosis in children with Type 1 Diabetes Mellitus (T1DM).

Background: The prevalence of CD among patients with T1DM is between 3-10%

Using a retrospective observational cohort with 63 children, the authors recommend raising the cut-off from performing biopsies from 3 times the ULN to 11 times ULN.

Here’s why:

  • This change in increases the specificity from 36% to 73% while reducing sensitivity from 96% to 87%.  In addition, this improves the positive predictive value from 88% to 94%, but lowered negative predictive value from 67% to 53%.  Overall, this leads to a reduction in “unnecessary biopsies.”
  • The authors note that while the serology sensitivity is reduced, it is still acceptable and justified because “normalization of elevated TG2A  can occur in up to one-third of patients.”
  • Another finding from this cohort was that 55% of children with Marsh 0 or 1 histology were symptomatic, indicating that symptoms are not specific for CD.

While the authors have recommended a higher threshold and advocated for repeating serology ~3 months later in those with lower titers, the associated editorial by Stefano Guandalini makes the following points:

  1. Raising the titer threshold would leave 13% of patients with celiac disease undiagnosed (or at least with a delay in diagnosis)
  2. “For lower titers, the physician will have to apply his or her knowledge and conscience in each individual case…we must be mindful of the serious risk of missing too many patients with celiac disease by applying a high threshold, a risk probably outweighing that of an unnecessary biopsy.”

My take: This study shows that in children with T1DM who have abnormal lower-value celiac serology, a careful discussion with parents is needed about the merits of endoscopy or deferring until persistent positivity.

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Taken near Hunley bridge, Isle of Palms, SC

Are Your Geneticists Looking For Celiac Disease in Children With Down Syndrome?

Briefly noted: E Liu et al. JPGN 2020; 71: 252-6Routine Screening for Celiac Disease in Children With Down Syndrome Improves Case Finding

  • Retrospective chart single center review of children with Down syndrome (2011 to 2017).
  • Prevalence of celiac disease in our population of children with Down syndrome ages 3 years or older was 9.8%.
  • 90 with celiac disease diagnosis:
    • 58 biopsy-confirmed
    • 17 with diagnosis via serology threshold in accordance with ESPGHAN
    • 9 diagnosis at outside center
    • 6 with serology but not meeting definitive criteria
  • 82% were identified through screening rather than clinical symptoms

My take: To identify celiac disease in children with Down syndrome, routine screening is needed.

Pictures from Sullivan’s Island, SC -This first picture looks out on Charleston Harbor and Ft Sumter is in the distance

Drug Therapy for Celiac Disease: Case Report

Briefly noted: L Waters et al. Annals Int Med 2020; doi:10.7326/L20-0497. Celiac Disease Remission With Tofacitinib

The authors describe a male with a well-documented case of celiac disease and alopecia areata.  He was placed on tofacitinib off-label for his alopecia areata and it was discovered that his celiac disease had developed “complete histologic and serologic remission…while he was still on a gluten-containing diet.”  Prior to medication, he had confirmation of both severe histologic changes and high tTG IgA titers.

The authors note that tofacitinib inhibits CD8+ T-cell mediated enteropathy in a transgenic mouse model.

My take (borrowed from authors): Tofacitinib has many potential adverse effects but may considered for further study, especially in refractory celiac disease.

Table –From Annals of Internal Medicine Twitter Feed

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For those interested in voting by mail in November -don’t miss the deadline!

Does The Degree of Villous Atrophy Affect Long-Term Outcomes with Celiac Disease? Plus One

S Kroger et al. JPGN 2020; 71: 71-7.  This study, conducted from 1966-2014, examined long-term outcomes of individuals diagnosed with celiac disease in childhood. This study examined 906 children and sent questionnaires to 503 adults (212 responded) who were diagnosed in childhood.

Key findings:

  • More recent diagnosis (after 2006) has been associated with children having milder lesions, more often diagnosis due to screening (rather than symptoms) 30% vs. 25%, less anemia (16% vs 21%), less growth disturbances (22% vs. 36%), and lower TTG-2 titers (mean 64 U/L vs 120 U/L.
  • Among adults completing questionnaire, severity of villous atrophy at childhood diagnosis did not predict complications, persistent symptoms, quality of life, or adherence with glute-free diet

RV Lopez et al. JPGN 2020; 71: 59-63. Influence of the 2012 European Guidelines in Diagnosis and Follow-up of Coeliac Children With Selective IgA Deficiency. This study showed that the guidelines were used incorrectly for individuals with selective IgA deficiency, using a 10-fold elevation of TTG IgG instead of TTG IgA. The associated editorial (pg 2 by P Gillett) recommends “we should perform endoscopy in all sIgAD patients.”  In addition, this population may merit followup endoscopy at much lower threshold due to difficulty using serology for follow-up.

My take: Children with severe villous atrophy due to celiac disease can respond fully to a gluten-free diet.  In the small subset of individuals with selective IgA deficiency, a no-biopsy diagnosis is not recommended.

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Study May Indicate Biologic Basis for Brain Fog in Persons with Celiac Disease

From The Onion: Dumbass Dog Wearing Face Mask All Wrong

From The Onion


A recent study (ID Croall, et al. Gastroenterol 2020; 158: 2112-22), using a UK Biobank with 500,000 adults, compared 104 participants with celiac disease to 198 healthy age-matched controls (mean age 63 years).

The authors examined cognitive outcomes, mental health outcomes and imaging data (MRI, diffusion tensor imaging).

Key findings: 

  • The celiac cohort had significant deficits in reaction time (P=.004), anxiety (P=.025), depression (P=.015), thoughts of self-harm (P=.025), and health-related unhappiness (P=.01)
  • Imaging studies showed white matter changes “which match up well anatomically with the regions affected in the celiac-related neurologic syndrome gluten ataxia.”

Limitations: study lacked data on celiac treatment status –whether better control or earlier diagnosis/treatment would reduce CNS complications is uncertain.  Also, whether these findings are more or less prevalent in individuals with undiagnosed celiac disease is unclear.

My take: This study provides further evidence that celiac disease results in significant neurologic problems and further reasons for those with celiac disease to adhere to a strict gluten-free diet (as other studies of neurologic outcomes indicate that a GFD can improve/reverse neurologic morbidities).

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Growth in Children at Risk for Celiac Disease & Emapalumab for Hemophagocytic Lymphohistiocytosis

Briefly noted:  R Auricchio et al. Archives of Disease in Childhood 2020; http://dx.doi.org/10.1136/archdischild-2019-317976. Growth rate of coeliac children is compromised before the onset of the disease Thanks to Mike Hart for the reference.

Methods:   We analysed the growth patterns of infants at genetic risk of CD, comparing those who developed CD by 6 years of age (CD ‘cases’, 113 infants) versus those who did not develop CD by 6 years (no CD ‘controls’, 831 infants).

Key finding: The growth of children at risk of CD rarely fell below ‘clinical standards’. However, growth rate was significantly lower in cases than in controls. Our data suggest that peculiar pathways of growth are present in children who develop CD, long before any clinical or serological signs of the disease appear.

F Locatell et al. NEJM 2020; 382: 1811-22. This open-label study (n=34) investigated emapalumab, a human anti-interferon-gamma antibody, for the treatment of primary hemophagocytic lymphohistiocytosis (HLH). Of the 26 patients who completed the study, approximately 65% had a response (based on clinical and lab features) and were able to proceed to transplantation.

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