Category Archives: Pediatric Gastroenterology Intestinal Disorder

How Gut Microbes Could Lead to Atherothrombotic Disease

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About three years ago, this blog looked at the link between gut microbes, diet, genes and heart disease (Linking diet, genes, and gut microbes to…heart disease | gutsandgrowth).

A summary of the most recent information on this topic: H Tilg. “A Gut Feeling About Thrombosis” (NEJM 2016; 374: 2494-6).

Background: Previous research has shown that certain dietary nutrients that include choline are processed by gut microbes to produce trimethylamine (TMA) which is converted into TMA-N-O (TMAO) by the liver.  Particular foods that have been associated with higher TMAO include meats and eggs.  It has been observed that antibiotics, presumably by their affect on gut microbes, reduce TMAO levels.

What’s new: Zhu et al (Cell 2016; 165: 111-24) “gave mice excess of dietary choline, microbe-generated TMAO enhanced platelet responsiveness in vivo, promoting a prothrombotic phenotype” was blocked by the administration of oral antibiotics.  Fecal microbiota transplantation, however, elevated the risk of thrombosis when administered to germ-free mice.

This data shows more clearly a causal relationship between TMAO and thrombotic mechanisms via platelet activation and a causal relationship between gut microbes and TMAO levels. However, this data does not determine exactly how we should modify our diets and or microbes to achieve improved clinical outcomes.

GutFeelingAbout

More than Two Years of Constipation Before Specialty Help

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A recent article (S Malowitz et al. JPGN 2016; 62: 600-02) examined the age of onset of constipation in a retrospective review of 538 children with functional constipation between 2012-2014.

Key findings:

  • Median age of onset was 2.3 years
  • On average, “2.7 years pass between the onset of functional constipation and a referral to a specialist.”  In the oldest quartile, the lapse between onset and referral was shorter, 1.8 years.  This may reflect the social consequences of soiling in school-aged children.

The authors note: “encouraging clinicians and parents to think of constipation as a chronic problem with physical and mental health implications may improve outcomes and quality of life for affected children.”

My take: The suffering and burden of constipation is easily overlooked in a busy primary care visit.  This is a shame because this is one area where inexpensive specialty care (i.e. minimal testing) can truly make a big difference.

Related blog posts:

Atlanta Zoo 2016

Atlanta Zoo 2016

 

 

What to Make of Post-op Treatment for Crohn’s Disease

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In 2009, Regueiro and colleagues published an influential paper “Infliximab prevents Crohn’s disease recurrence after ill resection” (Gastroenterol 2009; 136: 441-50). However, this was a small study with only 24 patients.  In this study, only 1 of 11 patients on infliximab had endoscopic recurrence compared with 11 of 13 of placebo patients at 1 year.  Besides the promising result that infliximab may prevent recurrent Crohn’s disease, this study confirmed that there is poor correlation between endoscopic recurrence and clinical activity scores.  In addition, the implication was that early treatment could be very important.

Now, a much larger study has been published (M Regueiro et al. Gastroenterol 2016; 150: 1568-78) and has cast some doubt on these earlier findings. It may have “muddied the waters” regarding the optimal approach.  The authors conclude that infliximab reduces postoperative endoscopic, but not clinical, recurrence of Crohn’s disease. Furthermore, they recommend in their discussion: “it may be reasonable to approach low-risk patients undergoing their first resection for CD conservatively and initiate treatment only if there is endoscopic recurrence at 6 months” [post-op].  The associated editorial (1521-24), after highlighting some of the important clinical findings, also says, that it may be “difficult to convince payers and patients that >2-4 years of treating an asymptomatic patient with TNFi, with its potential risks of long-term adverse effects, will be required to prevent clinically meaningful endpoints.”

Before accepting these conclusions, a closer look at the study is important.  This randomized study evaluated 297 patients at 104 sites. The study was intended to stop at 200 weeks, but was prematurely terminated at 104 weeks. Infliximab dosing was 5 mg/kg every 8 weeks.  This study was called the PREVENT study:  Prospective, Multicenter, Randomized, Double-blind, Placebo-Controlled Trial Comparing Remade and Placebo in the Prevention of Surgical Resection Who Are at an Increased Risk of Recurrence.

Key findings:

  • At week 76, clinical recurrence was not statistically different, though favored infliximab group: 12.9% vs. 20.0%
  • At week 76, endoscopic recurrence was less in infliximab-treated: 30.6% vs 60.0%
  • Also, more severe endoscopic recurrence  (Rutgeerts scores of i3 or i4) was markedly lower: 22.4% vs 51.3%

Other points:

  • Infliximab effectiveness could have been even higher if there had been an opportunity to escalate dosing; this occurs in about half of patients in typical clinical care.
  • This study’s focus on the primary outcome of clinical recurrence winds up overshadowing the much improved endoscopic results.

My take: I think that most well-informed patients and physicians would prefer to be treated post-operatively if they look at the results of this study closely.

From AGA twitter feed

From AGA twitter feed

Recognizing Reactive Arthritis due to Clostridium difficile

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A recent study shows that reactive arthritis can occur in children with Clostridium difficile infection and that recognition of this problem will improve management.

From JAMA Online First, DB Horton et al JAMA Pediatr. Published online May 16, 2016. doi:10.1001/jamapediatrics.2016.0217 (thanks to Ben Gold for this reference):

Abstract:

Importance  The incidence of Clostridium difficile infection has increased among children. The epidemiology of pediatric C difficile infection–associated reactive arthritis is poorly understood.

Objective  To characterize the incidence, recognition, and distinguishing clinical features of pediatric C difficile infection–associated reactive arthritis among children with C difficile infection.

Design, Setting, and Participants  In this cohort and nested case-control study using electronic health records from January 1, 2004, to December 31, 2013, across 3 geographically diverse pediatric health care networks, we screened for reactive arthritis among 148 children between ages 2 and 21 years with diagnostic or procedural codes suggesting musculoskeletal disease associated with C difficile diagnosis or positive testing. We identified 26 cases with acute arthritis or tenosynovitis within 4 weeks before to 12 weeks after confirmed C difficile infection with (1) no alternative explanation for arthritis and (2) negative synovial cultures (if obtained). Network-matched C difficile–infected controls without arthritis were randomly selected at the time of cohort member C difficile infections.

Main Outcomes and Measures  Incidence of C difficile infection–associated reactive arthritis was calculated based on (1) pediatric source population and (2) children with C difficile infection. Characteristics of cases and controls were compared using conditional logistic regression.

Results  Based on the cases identified within the source population of the 3 hospital networks, we estimated that C difficile infection–associated reactive arthritis incidence was 5.0 cases per million person-years (95% CI, 3.0-7.8). Reactive arthritis affected 1.4% of children with C difficile infection yearly (95% CI 0.8%-2.3%). Joint symptoms began a median of 10.5 days after initial gastrointestinal symptoms, often accompanied by fever (n = 15 [58%]) or rash (n = 14 [54%]). Only 35% of cases of C difficile infection–associated reactive arthritis were correctly diagnosed by treating health care professionals (range across centers, 0%-64%). Five affected children (19%) were treated for presumed culture-negative septic hip arthritis despite having prior postantibiotic diarrhea and/or other involved joints. Compared with controls, cases of C difficile infection–associated reactive arthritis were less likely to have underlying chronic conditions (odds ratio [OR], 0.3; 95% CI, 0.1-0.8). Although all cases had community-onset C difficileinfection and fewer comorbidities, they were more likely to be treated in emergency departments and/or hospitalized (OR, 7.1; 95% CI, 1.6-31.7).

Conclusions and Relevance  C difficile infection–associated reactive arthritis is an underdiagnosed, potentially morbid reactive arthritis associated with C difficile infection occasionally misdiagnosed as septic arthritis. Given the rising incidence of pediatric C difficile infections, better recognition of its associated reactive arthritis is needed.

Screenshot from JAMA website

Screenshot from JAMA website

In Case Someone Asks…Low FODMAP Maternal Diet May Help Colic

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According to a very small study, maternal ingestion of a low FODMAP diet reduced crying in colicy babies who were breastfed.  This report was presented at the recent United European Gastroenterology meeting (P0609).  The study consisted of a single-blind, open-label study of 18 infants.  The key finding was reduced crying from 142 minutes to 90 minutes over the 2 week study period.

A summary of this report is available at gastroendonews.com (May 2016, pg 8).

My take: A bigger study is needed to ascertain whether this intervention is worthwhile.  Many kids get better during a 2 week period without treatment.

NYT: Educate Your Immune System

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A recent commentary updates the concept of the hygiene theory and how our lack of exposures to a ‘dirtier’ environment when we are younger can make us more prone to autoimmune diseases, including celiac disease, diabetes, and multiple sclerosis.

Here’s the link: Educate Your Immune

Here’s an excerpt:

People living just over the border in Russian Karelia, as the region is known, have the same prevalence of genes linked to autoimmune disease [as in Finland]. They also live at the same latitude and in the same climate. And yet they have a much lower vulnerability to autoimmune disease. Celiac disease and Type 1 diabetes occur about one-fifth and one-sixth as often, respectively, in Russian Karelia as in Finland. Hay fever and asthma, allergic diseases that also signal a tendency toward immune overreaction, are far less common.

So in a follow-up study, the results of which appeared last month in the journal Cell, Dr. Xavier and his colleagues followed 222 children who were genetically at risk of developing autoimmune diabetes. The newborns were equally divided among Finland, Russia and Estonia, where the prevalence of Type 1 diabetes is on the rise, but still well below Finland’s.

Autoimmune diabetes can be predicted, to some degree, by the appearance of certain antibodies in the bloodstream that attack one’s own tissues. After three years, 16 Finnish children and 14 Estonian children had these antibodies; only four Russian children did. And when the scientists compared the children’s microbiomes in the three countries, they found stark differences. A group of microbes called bacteroides dominated in Finnish and Estonian infants. But in Russia, bifidobacteria and E. coli held sway….

Russian kids have more fecal oral infections, such as hepatitis A, suggesting more sharing not only of pathogens, but of microbes that may benefit health. And previous studies have found that Russian homes harbor a richer and more diverse community of microbes than Finnish ones….

The world today is very different from the one our immune system evolved to anticipate — not just in what we encounter, but in when we first encounter it. Preventing autoimmune disorders may require emulating aspects of that “dirtier” world.

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Best Fecal Marker for Crohn’s Disease: Calprotectin

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A recent study (EK Wright et al. Inflamm Bowel Dis 2016; 22: 1086-94) collected data from 135 participants in a prospective, randomized, controlled trial aimed at preventing postoperative Crohn’s disease (CD) recurrence.  As part of this study, serial stool collections enabled comparison of fecal markers: calprotectin (FC), lactoferrin (FL) and S100A12 (FS).

FC was the optimal marker and was superior to CRP and CDAI. Table 4 provides a list of sensitivity, specificity, PPV, and NPV for each of the fecal markers at various cutoffs.

For FC, using the optimal cutoff of 135 mcg/g, the sensitivity was 0.87, specificity was 0.66, PPV was 56%, and NPV 91%.  A lower cutoff (50 mcg/g) improved sensitivity to 0.96 and NPV to 94%; whereas a higher cutoff (200 mcg/g) lowered the sensitivity to 71% but improved the specificity to 0.74 along with raising the PPV% to 59%.

My take: While the yield of a test changes based on the population examined, this report indicates that it is likely that calprotectin would outperform the other fecal inflammatory markers in most settings.

Related blog posts:

Briefly noted: G Gale et al. Inflamm Bowel Dis 2016; 22: 1071-77.  This report describes more extensive disease when there is concomitant orofacial granulomatosis with Crohn’s disease.

Paris from Postcards

Paris from Postcards, Vik Muniz

ParisCaption

Identifying IBD Years Before Symptoms

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A while back there was a movie called “Minority Report.”  The movie’s premise was that crimes could be predicted and stopped before they occurred.  A recent study (P Lochhead et al. Clin Gastroenterol Hepatol 2016; 14: 818-24) presents intriguing data suggesting a similar scenario for inflammatory bowel disease (IBD).

The authors used a prospective, nested case control study of participants in the Nurses’ Health Study I and II. Median age of patients with Crohn’s disease (CD) (n=83) and ulcerative colitis (UC) (n=90) was 52.7 years and 50.4 years respectively. Key findings:

  • Median prediagnostic hsCRP levels (mg/L) were 2.3 in CD, 2.2 in UC and 1.5 in controls (n=344).
  • Median prediagnostic IL6 levels (pg/mL) were 1.7 in CD, 1.2 in UC, and 1.0 in controls.
  • Median time interval between blood collection and diagnosis was 6.6 years for CD and 6.8 years for UC.
  • There was increased odds for developing disease even after adjustment for potentially confounding variables like smoking.  This analysis held up even when excluding disease that developed within 2 years of sampling.

Overall, this study suggests that there is a significant population of patients with subclinical IBD which precedes the diagnosis by several years.  This report adds to a number of other studies showing potential “preclinical phase” of many diseases including rheumatoid arthritis and type 1 diabetes.

My take: It is fascinating that bloodwork can be abnormal years before clinical symptoms. However, as in “Minority Report” the problem will be with identifying a crime/disease that might never occur.

Unrelated –Chart Depicting Car Temps:

car temp

IBD School Videos for Patients and Families

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While these “IBD School” YouTube videos have been around for several years, I only became aware of them in the past few months.  I think they are good patient education resources.

Here are some links to a few of them:

There are a lot of these videos including the following:

My take: these videos are generally ~4 minutes and a good way to get a lot of information on IBD pretty quickly.

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False-positive Tissue Transglutaminase Antibodies

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While tissue transglutaminase IgA antibody is thought to have high specificity for celiac disease, other etiologies need to be considered. As an example, KR Schwartz et al. (NEJM 2016; 374: 1466-76) present a case report which describes a 12 year old who was diagnosed with lymphoma after presenting with anemia, abdominal pain, and fevers. One interesting point was the elevated tissue transglutaminase IgA antibody of 74 (0-15) at presentation; endomysial antibody was negative. The TTG IgA normalized with treatment. The authors note that the presence of TTG IgA antibodies “is not specific for celiac disease but rather is a general phenomenon related to mucosal lesions.”

Related blog posts:

EricCarleCatepillar