Celiac Disease and Mode of Delivery -Perhaps Not Very Consequential

Briefly noted:

A recent study (E Lionetti et al. J Pediatr 2017; 184: 81-6) did NOT find an association between mode of delivery and the development of celiac disease (CD).

After a telephone interview to confirm mode of delivery, the authors identified 431 children at high risk for CD and compared the rates of celiac autoimmunity (serology-positive) and overt CD that developed by age 5 years:

  • CD autoimmunity –cesarean vs vaginal:  24% and 19% (P=.2)
  • Overt CD –cesarean vs vaginal:  19% and 14% (P=.2)

While neither reached statistical significance, there was a higher rate in those born by cesarean mode.  The lack of a statistical association could be a reflection on sample size or the specific population that was studied.  However, more likely, this suggests that “the role of intestinal microbiota at birth in the pathogenesis of immune mediated disorders has been overestimated.”

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Caution with Celiac Genetic Testing Plus Two

Conventional wisdom and previous studies have indicated that negative testing for HLA-DQ8 and HLD-DQ2.5 alleles makes a diagnosis of celiac disease (CD), now or in the future, very unlikely.  While ~60% of the population has one of these alleles, testing negative for these alleles has been regarded as having a high negative predictive value (>99%) and can be valuable in cases of equivocal diagnosis.

The authors of recent report (F Fernandez-Banares et al. Clin Gastroenterol Hepatol 2017; 15: 594-96) challenged this wisdom, noting that there is expected to geographical variation in the presence of these alleles. The goal of their study was to assess the prevalence of HLA-DQ2.5/8 among CD patients in Spain by reviewing previous studies; 12 studies were included. To be included, patients had to have villous atrophy, positive serology and available genotyping.

Key finding:

  • Among 2963 Spanish CD patients, 3% “might be negative for HLA-DQ2.5/8.”

This is a brief report.  It is expected that limitations would relate to the accuracy of genotyping and of excluding other causes of villous atrophy.

My take: (from the authors) “This information highlights the need to be cautious when ruling out CD only on the basis of genetics.”

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Briefly noted:

L Kivela et al. J Pediatr 2017; 183: 115-21.  This study divided children with CD into those identified via screening (n=145) and those identified due to clinical symptoms (n=359). Key findings:

  • There were no differences in serology or histology between the two groups
  • More than half (51.8%) of screen-detected patients had symptoms at diagnosis, but typically these were milder than in the clinically-detected group.
  • Anemia was more common in the ‘clinical group’ 22.9% vs 7.1% (screen group) as was poor growth (36.9% vs. 15.7%).

AJ Irvine et al. Am J Gastroenterol 2017; 112: 65-76. (Thanks to Ben Gold for this reference) In this systemic review with 15,256 individuals (& 9,275 with irritable bowel), “prevalence of positive celiac serology and biopsy-proven CD was significantly higher in subjects with symptoms suggestive of IBS vs. healthy controls.”  The odds ratio for serology-positive and/or biopsy-proven CD ranged from 2.75 to 4.48, though there was no significant increase in these ORs for North American studies.

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Celiac Disease and Psychological Problems

A recent study (A Butwicka et al. J Pediatr 2017; 184: 87-93) describes an increased rate of childhood psychiatric disorders among children with celiac disease (CD).

The authors used a nationwide registry (in Sweden) with 10,903 children with celiac disease, 12,710 siblings, and more than 1 million control patients. The median age at diagnosis was 3 years and median duration of followup was 9.6 years.

Key findings:

  • CD patients had a 1.4 fold greater risk of psychiatric disorders, including mood disorders, eating disorders, behavioral disorders, and ADHD.
  • CD siblings did not have an increased risk.
  • 7.7% of children with CD were diagnosed with a psychiatric disorder

Limitation: The actual reported incidence of psychiatric disorders seems low in both the CD patients and controls.  It is possible that some of the difference could be related to selection bias. Patients with (undiagnosed) psychiatric disorders may be more likely to be anxious, and seek out medical attention for their GI complaints;  this could precede a diagnosis of CD.

Strengths: This study has large numbers of patients and the data was prospectively obtained.

The association with increased psychiatric problems could have a biologic basis or be related to the toll of chronic gastrointestinal symptoms prior to diagnosis and the difficulty of managing CD.

My take: This is an intriguing study and suggests that patients with CD are more likely to be diagnosed with a psychological disorder.  Whether CD itself or the preceding symptoms trigger this diagnosis is uncertain.

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Abdominal Pain -Placebo Effect and Celiac Effect

Briefly noted:

  • DR Hoekman et al. J Pediatr 2017; 182: 155-63.
  • M Saps et al. J Pediatr 2017; 182: 150-54.

In the first study, Hoekman et al identified 21 studies to determine the placebo response in pediatric abdominal pain-related functional GI disorders.  The authors found a pooled response to placebo of 41% (improvement) and resolution with placebo occurred in 17%.

The second study examined 289 children (55% U.S., 45% Italy) comparing the frequency of functional GI disorders in children with celiac disease on a gluten free diet compared with controls.  Overall, chronic abdominal pain was present in 30.9% of subjects with celiac disease compared with 22.7% of sibling controls and 21.6% of unrelated controls. This did not reach statistical significance.

Related post: Is functional pain more common with celiac disease?

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Latiglutenase Not Effective for Celiac Disease, Plus One

A recent study (JA Murray et al. Gastroenterol 2017; 152: 787-98) examined the effectiveness of  latiglutenase for celiac disease.  Latiglutenase (aka ALV003) is an oral medicine which is a mixture of two recombinant gluten-targeting proteases.

The concept of latigluenase is that a medicine that degrades the gluten protein could obviate the need for a gluten free diet.  Unfortunately, in this study with 494 patients with celiac disease for at least 1 year, the medicine at various doses for 12 to 24 weeks was ineffective. There was no difference between the medicine and placebo with regard to villous height:crypt depth ratio, number of intraepithelial lymphocytes or serologic markers of celiac disease.  Symptom scores increased in both the active treatment group and the placebo group.  While this was a negative study, the authors did note some effect on symptom domains on higher dosing regimens. “This observation suggests that treatment with latiglutenase may affect symptoms before showing clinically meaningful effects on serologic and histologic end points.

A second study (RS Choung et al. Gastroenterol 2017; 152: 830-9) examined prevalence and morbidity of undiagnosed celiac disease in Olmstead County. After excluding patients with celiac disease, sera from 30,425 adults and 830 children were tested for tissue transglutaminase IgA antibody (tTG)  and endomysial antibody (EMA).  Case definition: patients were considered to have celiac serologically if tTG titer was 2.0 U/mL or greater with a positive EMA. The prevalence of celiac disease was 1.1% in adults and 1.0% in children. The majority of patients with celiac disease (>80%) have not received the diagnosis.  By comparing those with positive celiac serology to matched controls (2 controls for each positive), the authors determined that undiagnosed celiac disease was associated with increased rates of hypothyroidism (OR 2.2) but no other significant morbidities.  Median followup period was 6.3 years.

My take: A promising new therapy for celiac disease, latiglutenase, looks like it will not be effective and there are a lot of individuals with celiac disease who are unaware of their diagnosis.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

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USPSTF Takes Neutral Stance on Celiac Disease Screening in Asymptomatic Individuals

Full Text: JAMA. 2017;317(12):1252-1257. doi:10.1001/jama.2017.1462

From Abstract:

Objective  To issue a new US Preventive Services Task Force (USPSTF) recommendation on screening for celiac disease.

Evidence Review  The USPSTF reviewed the evidence on the accuracy of screening in asymptomatic adults, adolescents, and children; the potential benefits and harms of screening vs not screening and targeted vs universal screening; and the benefits and harms of treatment of screen-detected celiac disease. The USPSTF also reviewed contextual information on the prevalence of celiac disease among patients without obvious symptoms and the natural history of subclinical celiac disease.

Findings  The USPSTF found inadequate evidence on the accuracy of screening for celiac disease, the potential benefits and harms of screening vs not screening or targeted vs universal screening, and the potential benefits and harms of treatment of screen-detected celiac disease.

Conclusions and Recommendation  The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for celiac disease in asymptomatic persons. (I statement)

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Celiac Diseaase and Diabetes

A recent review (B Weiss, O Pinahs-Hamiel. JPGN 2017; 64: 175-79) of the medical literature describes the various recommendations regarding celiac disease (CD) and type 1 diabetes mellitus (T1DM).

Key points:

  • Two-thirds of patients with T1DM and CD are asymptomatic for CD at diagnosis
  • Many children with T1DM and with positive CD serology may normalize the serology spontaneously.   In one study with 446 children with T1DM who were screened for CD, 38 had persistently abnormal serology whereas 27 had fluctuations in CD serology.  In another study with 738 children, of 48 patients with positive CD serology, normalization was evident in 35% at 1 year.

The authors review recommendations for CD screening.  Several guidelines have recommended soon after diagnosis (especially if >2 years of age).

screenshot-149

Their figure 1 algorithm provides guidance on evaluation.  In those patients with T1DM and positive CD serology, if they are asymptomatic, assuring that serology is persistently elevated may be worthwhile before proceeding with small bowel biopsy.  In those who initially test negative for serology, there may be a role for HLA testing and/or periodic screening every few years.

Related editorial on recent article: Celiac Disease, Gut-Brain Axis, and Behavior: Cause, Consequence or Merely Epiphenomenon (A Fasano)  Thanks to KT Park for this reference.  Excerpt:

By assessing the psychological functioning of infants enrolled in the Environmental Determinant of Diabetes in the Young trial and followed prospectively, the authors reported that 3.5-year-old children affected by celiac disease autoimmunity (CDA), defined as positive serology in children at risk, have increased reports of depression/anxiety, aggressive behavior, and sleep disturbances. Interestingly, these symptoms were significantly greater in the 66 children with CDA whose mothers were unaware of the diagnosis compared with the 440 children with CDA whose mothers were aware of the diagnosis and the 3651 children without CDA, decreasing the chance that the reported behaviors were biased by families’ subjective assessment…Prospective studies such as that reported by Smith et al may be a key approach to shedding light on how intestinal factors can influence human behavior and to identifying possible targets to ameliorate psychological symptoms caused by inappropriate gut-brain cross-talk.

Reference articleSmith L, et al.. Psychological manifestation of celiac disease autoimmunity in young children. Pediatrics. 2017;139(3):e20162848

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.