Celiac Disease and Mode of Delivery -Perhaps Not Very Consequential

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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

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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.

Palace of Versailles

 

Celiac Disease and Psychological Problems

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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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Take Two: 1. Mushroom Poisoning 2. Maternal Deaths with Childbirth

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The link to the NPR article at the bottom of this blog is highly recommended –though it is a fairly long report.  Sad story for Mother’s Day.

First, from AGA blog summary of recent article: Which Patients Are at Greatest Risk From Mushroom Poisoining

An excerpt:

Maurizio Bonacini et al collected data from 27 patients (15–82 years old) admitted to the emergency department within 24 hours of ingesting wild mushrooms. All presented with nausea, vomiting, abdominal cramps or pain, and diarrhea…

Twenty-three patients survived without liver transplantation, 1 woman underwent liver transplantation on day 20 after mushroom ingestion, and 3 women died of hepatic failure.

Of the 23 patients with peak levels of total bilirubin of 2 mg/dL or more during hospitalization, 4 died or required liver transplantation.

A peak serum level of AST <4000 IU/L identified patients with good outcomes (survival without need for liver transplant) with 100% positive predictive value; use of this cutoff would have saved 10 patients from a transfer to our tertiary center.

Bonacini et al also found that a peak INR value of <2, or a nadir factor V cutoff ≥30%, would have avoided transfer for 7 and 6 patients, respectively.

Also from NPR: Focus on Infants Leaves U.S. Moms in danger

FDA Warning on Eluxadoline (Viberzi)

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Briefly noted: The FDA has issued a safety warning for patients with irritable bowel syndrome who have had their gallbladder removed.

FDA Warns of Increased Risk of Serious Pancreatitis with irritable bowel drug eluxadoline (Viberzi) in patients without a gallbladder

An excerpt:

Viberzi is a prescription medicine used to treat irritable bowel syndrome in adults when the main symptom is diarrhea (IBS-D)…From May 2015, when Viberzi was first approved, through February 2017, FDA received 120 reports of serious cases of pancreatitis or death.* Among the 68 patients who reported their gallbladder status, 56 of them did not have a gallbladder and received the currently recommended dosage of Viberzi. Seventy-six patients were hospitalized, of which two patients died.

My take: Now that this warning has been issued, there may be additional cases identified. While this medication is mainly used in adults, pediatric gastroenterologists need to be aware of this risk in counseling potential patients.

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Science in a Hyperpartisan Age

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Two recent commentaries (L Rosenbaum. NEJM 2017; 376: 1607–09; DJ Hunter et al. NEJM 2017; 376: 1605–7) discuss the intersection of science and politics.

Some key points from the first commentary:

  • “When doubt is wrapped up in one’s cultural identity or powerful emotions, facts often not only fail to persuade, but may further entrench skepticism.”  This is referred to as “biased assimilation.”
  • People with “higher levels of science comprehension are actually also the most adept at dismissing evidence that challenges their beliefs.”  Liberals, “for instance, are far more likely than conservatives to dismiss science suggesting that genetically modified foods are safe.”
  • “It’s easy to forget that most scientific facts, and related policies, don’t induce tribalism. You don’t see partisan battles over treatment for myocardial infarction.”
  • Dan Kahan, an expert on the way emotion and identity affect our interpretation of scientific facts says that our president “is our science communication environment polluter in chief.”  Such polluters “cunningly incite cultural battles that ultimately heighten distrust of science.”
  • For vaccine skeptics, if criticized, will try to elicit a backlash against the “academic elite.”

The second commentary focuses on the issue of climate change.  Key points:

  • “Average temperatures have increased by 1.3 to 1.9 degrees F over the past century…and increases have accelerated in recent years…the three hottest years recorded in the U.S. were 2012, 2015, and 2016.”
  • Summer heat waves increase mortality, worsen mosquito-related diseases, jeopardize crop production, increase ozone which worsens lung function, and contribute to forest fires.  Increases in “extreme heat leads to more aggression and violence.”
  • Climate change increases severe storms like hurricanes and cause indirect effects like waterborne-disease outbreaks.
  • The authors advocate for the CDC’s Building Resilience against Climate Effects (BRACE) (https://cdc.gov/climateandhealth/)
  • “U.S. leadership is critical to global action. Jobs in the renewable energy sector…already outnumber those in power generation from coal, natural gas, and oil combined.”
  • “Climate change has become unnecessarily politicized.” Tools for discussing this topic: http://climateforhealth.org/lets-talk -1 hour webinar available and links to specific ways to make an impact.

My take:  While I concede that I am not an expert on this topic, it is clear that climate change is having effects on population health and there are ways to reduce the future impact. Please don’t call me an elitist.

 

 

Is Propofol Safe in Pediatric Patients with Food Allergy and Eosinophilic Esophagitis?

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According to a recent study (P Mehta et al. JPGN 2017; 64: 546-49), propofol was safe in pediatric patients with eosinophilic esophagitis (EoE) and food allergy.

This finding was based on a retrospective study of 1365 upper endoscopies (2013-2014).  Though, propofol was used less frequently, “there was no difference in complication rates relative to propofol use.”

Specifically, egg or soy allergy patients had 38 procedures; 114 children had EoE (without known egg or soy allergy) and 27 and EoE and egg or soy allergy.

This study is important because propofol is used frequently in patients with egg and soy allergies despite a contraindication warning on the package insert. Nevertheless, this study does not provide a definitive answer due to the very low rates of allergic reactions to propofol (~1:10,000 to 1:20,000).  In addition, the diagnosis of food allergy in this study relied on review of the medical record.

My take: This study is limited in scope but did not identify any significant safety concerns with propofol in patients who had EoE and/or egg/soy allergies.

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CMV in IBD: Tissue Matters

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A recent study (P Tandon et al. Inflamm Bowel Dis 2017; 23: 551-60) was a systemic review regarding the accuracy of blood-based testing for predicting colonic CMV reactivation in patients with inflammatory bowel disease.  The review identified 9 studies.  The overall sensitivity of blood-based testing (either pp65 antigenemia or blood PCR) for CMV was 50.8% and the specificity was 99.9%. Blood PCR was better at 60% sensitivity.

My take: Blood-based tests are not sensitive enough to exclude colonic CMV reactivation. The authors recommend the use of immunohistochemistry or tissue PCR for detecting CMV reactivation in inflammatory bowel disease.

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Two for the PPI Team

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Medicine safety is not nearly as straight-forward as most people would expect.  Virtually all medicines have the potential for adverse reactions.  In addition, there are often conflicting reports on how frequent adverse reactions occur; furthermore, negative studies demonstrating safety may be published less frequently due to publication bias.

This problem is compounded by the frequent misunderstanding of statistics.  Frequently, risks of medications are expressed as an odds ratio.  So, if an adverse reaction occurs twice as often with the medication than without the medication, the odds ratio would 2.0.  Yet, if the adverse reaction is rare (eg. one in a million), then the absolute increase in risk remains minuscule.

Proton pump inhibitors have received a lot of press, often about rare increases in adverse reactions. But, there are many potential benefits to these medications and numerous studies demonstrating fairly good safety profiles.  A few more studies (thanks to Ben Gold for these references) on their safety have recently been published:

  • 1. “Long-term Proton Pump Inhibitor Use is Not Associated with Changes in Bone Strength and Structure” LE Targownik et al. Am J Gastroenterol 2017; 112: 95: 101.
  • 2. “Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit.” DM Faleck et al. Am J Gastroenterol 2016; 111: 1641-8.

In the first study, the authors examined 52 PPI-users (>5 yrs) and 52 non-PPI users with mean age of 65 years.  They underwent quantitative CT , DXA, and markers of bone metabolism. “There were no differences detected..between the two groups.”  The conclude that PPIs were not associated with changes that increase a risk of fracture and “provide further evidence that the association between PPI use and fracture is not causal.”

In the second study, the authors analyzed data from 14 ICUs 2010-2013 and identified 18,134 patients (mean age 66-67 yrs) who met inclusion criteria.  271 (1.5%) developed Clostridium difficile infection (CDI) in the ICU.  The main risk factor for CDI was antibiotics with adjusted Hazard Ratio (aHR) of 2.79.  “There was no significant increase in risk for CDI associated with PPIs in those who did not receive antibiotics (aHR 1.56; 95% CI, 0.72-3.35).”  “PPIs were actually associated with a decreased risk for CDI in those who received antibiotics (aHR 0.64; 95% CI 0.48-0.83).”  The authors also noted that even those who received the highest doses of PPIs, “there was no risk for health-care facility-onset CDI.”

My take: PPIs can be life-saving medications and can alleviate a lot of suffering.  These studies pushback on some of the concerns about PPI risk.

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Correlation between Microbiome and Irritable Bowel Syndrome

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I vaguely remember jokes that I heard as a teenager about computers that could analyze stool or urine and then come to remarkable conclusions about the person’s health or extramarital problems.  Fast-forward a few decades and these jokes are not so far off.

A recent study (J Tap, M Derrien, et al. Gastroenterol 2017; 152: 111-23) describes an intestinal microbiome ‘signature’ associated with severity of irritable bowel syndrome (IBS).  Thanks to Ben Gold for highlighting this article.  (He placed this one on my desk: “Jay -FYI -It is all about the poop!”)

In this study, the authors collected fecal and mucosal samples from adult patients who met Rome III criteria for IBS.  They started with an exploratory set of 149 subjects (110 with IBS, 39 controls).  Subsequently, they used a validation cohort of 46 subjects (29 with IBS, 17 controls).

Key findings:

  • “By using classic approaches, we found no differences in fecal microbiota abundance or composition between patients with IBS vs healthy patients.”  But, “a machine learning procedure, a computational statistical technique, allowed us to reduce the 16S ribosomal RNA data complexity into a microbial signature for severe IBS, consisting of 90 bacterial operational taxonomic units.”
  • This microbial signature showed IBS to be associated negatively with microbial richness, exhaled CH4, presence of methanogens, and enterotypes enriched with Clostridiales or Prevotella species.  Figure 6 provides a graphic summary of the study and the microbial signature.
  • The authors note their findings were not explained by differences in diet or medications.
  • Overall, the microbial signature has a low sensitivity and thus at this point does not have clinical applicability.

My take: There are a number of studies showing that our gut microbiome is associated with numerous conditions, including IBS, inflammatory bowel disease, and metabolic syndrome.  Having our poops analyzed by a computer to tell us what is wrong does not seem all that funny anymore.

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