Author Archives: gutsandgrowth

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About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

Fluctuating Elastase Levels in Infants with Cystic Fibrosis

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A recent study sheds light on the variability of elastase levels in both pancreatic sufficient (PS) and pancreatic insufficient (PI) infants with cystic fibrosis (CF) (J Pediatr 2013; 162: 808-12).

After eliminating infants who did not have elastase values prior to 3.5 months and after 9 months, the study consisted of 61 formula-fed infants who had been diagnosed with CF.  Diagnosis was established based on either a positive sweat test or having two known CF mutations.

Background: Pancreatic elastase is produced by pancreatic acinar cells and is not degraded during intestinal transit.  It can be measured while on pancreatic enzyme replacement therapy (PERT) because it is specific for human elastase rather than porcine elastase.  In addition, samples are stable at room temperature for weeks.

Among this cohort, 28 (46%) were homozygous for the F508del mutation. Infants were part of a large docosahexaenoic acid (DHA) study; as such, they were randomized to receive either standard formula or formula supplemented with DHA.  Monthly stool samples were collected.

Results:

  • Of 29 infants with initial fecal elastase <50 mcg/g, all had a value <200 mcg/g at one year.  However, 3 had a value >200 mcg/g at some time during the first year of life.
  • Of 36 infants with initial elastase <100 mcg/g, 32 had a level <100 mcg/g at 1 year.  Only one infant in this group had a value consistent with PS and this infant had a mutation associated with increased likelihood of PS.
  • Of 12 infants with initial values between 100-200 mcg/g, more variability was noted in their multiple samples.  This group accounted for the majority of infants who were reclassified from PI initially to PS after one year of life.  Among all 48 with values <200 mcg/g, 4 were considered PS at final evaluation.  However, 13 had values >200 mcg/g at some point.
  • 13 infants were considered PS at initial evaluation with a value >200 mcg/g.  At the study conclusion, 3 had values <180 mcg/g.
  • The majority of fluctuation in elastase values occurred during the first 6 months of life.

These results lead to the following conclusions:

  1. Fluctuations in elastase levels during the first year of life indicate that some infants with PS become PI and vice versa.  Retesting at one year of life is important.
  2. The authors recommend that all CF patients with elastase values below 200 mcg/g receive PERT.
  3. One can extrapolate these findings to other populations.  A single normal or abnormal elastase value may not indicate ultimately whether a patient will remain pancreatic insufficient or sufficient. Though, values <50 mcg/g are more likely to indicate persistent PI status.

The authors do provide some speculation regarding these fluctuations.  They note that “a fecal elastase obtained very early in life might not reflect the child’s true functional pancreatic status.  Intestinal mucosal damage can cause secondary pancreatic insufficiency by decreasing signaling of the pancreas from enteroendocrine cells.”

Related blog links:

References:

  • -JPGN 2007; 44: 219.  Use of elastase in CF.  Pancreas secretes elastase; not degraded & does not cross react with porcine elastase, thus allowing measurement even in individuals on enzyme treatment.  Excellent sensitivity/specificity.
  • -J Pediatr 2004; 145: 322 & 285,  A fecal elastase-1   >100mcg/g has a 99% predictive value for excluding pancreatic insufficiency.
  • -JPGN 2003; 36: 314, 392.  Fecal elastase-1 is marker for exocrince pancreatic function & enteropathy.
  • J Peds 2009; 155: supplement. Clinical practice guidelines for infants/children <2 years of age with CF:
  1. -routinely give salt 1/8-1/4tsp/day
  2. -measure elastase & supplement if PI
  3. -Dose: 2000-5000 units lipase per feed –can go as high as 2500 units/kg (max daily 10000 units/kg/day)
  4. -monitor & supplement ADEK
  5. -consider 7% saline Rx & azithromycin in symptomatic

How to gain too much weight –attend daycare?

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According to a provocative study (J Pediatr 2013; 162: 753-8), receiving childcare as opposed to parental care was associated with increased weight.

1649 children were enrolled in a prospective birth cohort in Quebec.  Information about childcare was completed by their mothers at ages 1.5, 2.5, 3.5 and 4 years.  In addition, body mass index (BMI) was checked at ages 4, 6, 7, and 10 years of age.

Compared with care at home, children who attended a center-based childcare or were cared for by a relative were at increased risk of being overweight or obese, with odds ratios of 1.65 for center-based care and 1.5 for relative-based care.  Furthermore, increased hours away from home was associated with increased odds; every 5 hours increased the likelihood by 9% in the first decade of life.

These associations could not be explained by a number of potential confounding factors including socioeconomic status, breastfeeding, maternal employment, and maternal BMI (along with many other factors). In addition, the authors note in their discussion that these results are in line with other large studies from a number of countries.  One hypothesis for relative-based care has been that this may involve less physical activity, especially by grandparents.

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Seeing is Believing

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As noted in a recent blog (Food Marketing Detectable on Functional MRI | gutsandgrowth), functional MRI is being studied for a number of applications.  Now, more data has emerged that a “pain signature” can be identified with this technology (NEJM 2014; 368: 1388-97).

Using a series of experiments, the authors enrolled 114 healthy participants and ultimately identified an imaging signature that was associated with heat-induced pain and increased nonlinearly with increasing stimulus intensity.  The first part of the study involved a machine-learning analyses after inducing physical pain by applying heat to the forearm of the participants.  The sensitivity and specificity were 94% or more in discriminating painful heat from nonpainful warmth, pain anticipation, and pain recall.  In the fourth part of the study, the authors showed that the signature response was reduced when an opiod analgesic (remifentanil) was administered.

Because this study enrolled otherwise healthy patients, the results cannot be extrapolated to other populations.  Nevertheless, it is likely that other painful conditions will have unique functional MRI signatures.

Pain is not easy to ascertain and obtaining functional MRIs is not likely to have a role in the near future as a clinical tool.  The concept of identifying a measurable pain biomarker though has been strengthened by this study.

Related blog entry:

Pain changes brain | gutsandgrowth

Websites recommended by GI families

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Some useful websites that I recommend have been identified by patient’s or their families. They include the following:

As an unrelated aside, a recent commercial might be of interest to anyone who enjoys a little ‘potty humor:’  Kmart’s ‘Ship My Pants’ Commercial [HD] – YouTube

Related blog post:

Oley: Check it out | gutsandgrowth

Paris Classification of Pediatric Crohn’s Disease

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A recent study described the phenotypic results of a prospective, web-based registry of new-onset pediatric inflammatory bowel disease (IBD) in 17 European countries and Israel (Inflamm Bowel Dis 2013; 19: 378-85).

The EUROKIDS Registry included 582 pediatric Crohn’s Disease (CD) patients classified according to Paris classification:

  • 16% with L1 involvement of the terminal ileum only
  • 27% with L2 colonic involvement only (more common in younger children)
  • 53% with L3 involvement of the ileum and colon
  • 4% with L4 isolated upper GI disease.  Upper tract disease can be further subdivided into L4A esophagogastric disease and L4B jejunal/proximal ileal disease.
  • *Upper GI disease can coexist with L1, L2 or L3.  In this study, 34 (6%) had esophageal involvement, 102 (18%) had gastric involvement, and 100 (17%) had duodenal involvement.
  • In this study, 165 of the 507 patients did not undergo small bowel imaging. Of those who did, 64% had small bowel follow-through, 38% had MRI, 6% CT, and 5% video capsule.

Other findings:

  • Perianal disease (e.g.. fistula or abscess) noted in 9% at diagnosis.
  • Granulomas were found in 43% of patients who had biopsies from at least 10 segments of the GI tract
  • 82% of CD patients had nonstricturing, nonpenetrating disease (B1), 12% had stricturing disease (B2) and 5% had penetrating disease (B3).  2% had both stricturing and penetrating disease.
  • Extraintestinal manifestations were seen in 20% of the study population.
  • The authors estimated that the diagnostic yield of upper endoscopy  in the workup for pediatric IBD was  7.5% and for intubation of the ileum/ileoscopy 13%.

Study limitations included a selection bias of centers and pediatric gastroenterologists with a special interest in IBD.  Also, in this registry, older adolescents are underrepresented. In about one-third of the centers, patients older than 15 years are seen primarily by adult gastroenterologists.

Don’t Fix What’s Not Broken

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A recent study provides information about elective switching from infliximab (IFX) to adalimumab (ADA) in stable Crohn’s disease (CD) (Inflamm Bowel Dis 2013; 19: 761-66).  As a practical matter, patients and families inquire about switching therapy due to potential convenience and flexibility.  Thus far, there is little data to guide clinicians.  As such, the authors explored this question by designing an open-label study which would allow enrollment of any patients who had stable disease for >6 months (Harvey-Bradshaw Index ≤ 8) on IFX therapy.

In total, 29 patients with CD were enrolled with an average age of 39.  Twelve had previous resections.

Key results:

  • 21 patients (72%) were able to remain on ADA at 54 weeks.  8 patients discontinued ADA due to disease activity (n=3), side effects (n=4), or other symptoms (n=1).
  • 4 patients were restarted on IFX therapy; 1 required dose intensification.
  • At 54 weeks, 13 patients indicated a preference for IFX due to efficacy (n=9) or safety profile (n=4).  12 patients indicated a preference for ADA.  4 patients had no preference.

The authors state that a recommendation to avoid elective switching.  In their study, 28% were not able to be maintained on ADA therapy, more patients preferred IFX after experiencing both therapies, and switching back to IFX has been associated (in some) with reduced efficacy.  The main concern with an elective switch is the potential loss of response with very limited therapeutic alternatives.

The authors note that their study showed better results with an elective change than a previous study (the SWITCH trial, n=73).  In the SWITCH trial, “elective switch from IFX to ADA in patients with stable CD led to 47% of patients requiring dose intensification or interruption of treatment” in the ADA arm compared with 16% of patients who continued IFX therapy.  (Adalimumab in Crohn’s Disease Controlled by Infliximab)

The better outcomes in the current trial may have been due to selection of patients with milder disease and the more frequent use of concomitant immunosuppression.  In the current trial, 52% had concomitant immunosuppression (48% thiopurine, 4% methotrexate); in contrast, only 17% received concomitant immunosuppression in the SWITCH trial.  Another important difference was that the patients in the current trial received 160-80 loading doses rather than 80-40 induction.  Also, the trial designs were different.  The current trial enrolled patients without randomization; in contrast, the SWITCH trial randomized some patients to continue IFX and others to change to ADA therapy.

Related reference:

  • -Gut 2012; 61: 229-34. SWITCH trial.

Related blog references:

Food Marketing Detectable on Functional MRI

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The applications of functional magnetic resonance imaging (MRI) are burgeoning.  One recent usage has been on the effect of food logos on brain activation in obese and healthy children (J Pediatr 2013; 162: 759-64 & editorial 672-73).

After a pilot validation study to select food and nonfood logos, the authors recruited 10 healthy children with mean body mass index (BMI) at 50th percentile and 10 obese children with mean BMI at the ~98 percentile.  After completing reports on measures of self-control, the children underwent functional MRI while viewing food and nonfood logos.

The key findings were that healthy weight children, when viewing food logos, demonstrated greater activation in brain regions associated with cognitive control/self-control including Brodmann’s area 10 and the inferior frontal gyrus bilaterally.  Obese children showed greater activation in ‘reward’ regions of the brain when shown food logos.

While these studies should be considered preliminary due to the small sample size, they are intriguing nevertheless.  The editorial takes these findings and places them into context.

  • Children view ~6000 commercials annually; the majority feature calorie-dense and nutrient poor foods
  • “Any food can be marketed in any way, to any age group, and even the most vulnerable demographic groups can be targeted.”
  • “It is tempting to suggest interventions…to help resist marketed foods.”  However, the author notes that this strategy will fail due to increases in the “toxic influence” of advertising.
  • “Food brands are already commonplace in …sporting facilities, schools..in online advergaming..and in social media.”
  • “Targeted advertising has been related to greater consumption of high-calorie foods (eg. fast foods) by African-American and Hispanic children”
  • Policy initiatives “to turn back the tide of childhood obesity” are needed; studies that show a direct impact on children’s brains may be persuasive in compelling change.  Without these changes, companies will continue doing neuroscience research and will exploit their findings.

Bottom-line:  If one uses an analogy to tobacco, it is not quite 1964 for the food industry.

“In 1964 the Surgeon General of the U.S. (the chief doctor for the country) wrote a report about the dangers of cigarette smoking. He said that the nicotine and tar in cigarettes cause lung cancer. In 1965 the Congress of the U.S. passed the Cigarette Labelling and Advertising Act. It said that every cigarette pack must have a warning label on its side stating ‘Cigarettes may be hazardous to your health.'” History of Tobacco – Health & Literacy Special Collection

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Trouble Sleeping and Gastroesophageal Reflux

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Determining whether reflux is causing an infant to have trouble sleeping is quite difficult as a practical matter.  A recent retrospective study adds information to this topic but opens up a can of worms (JPGN 2013; 56: 431-35).

The main problem is that clinical reflux occurs in the majority of infants and that sleeping problems are ubiquitous as well.  This leaves the door open to testing a lot of infants. At the  same time, effective therapeutic options are limited.  So, identifying that reflux is causing trouble sleeping, when feasible, may be akin to getting the license plate of the truck that ran you over.

In this retrospective study (2008-2010) of 24 infants with a median age of 5 months, 18 were receiving acid-suppressing medications prior to evaluation.  Determination that reflux was causally associated with awakenings and arousals was determined with symptom association probabilities (SAP) based on 2-minute measurement intervals with multichannel intraluminal impedance/pH monitoring/simultaneous polysomnography; SAP was considered significant if ≥95%.

Findings: Seven patients had a positive SAP for arousals due to GER (5 exclusively related to non-acid GER).  Nine patients had a positive SAP for awakenings due to GER (4 exclusively related to non-acid GER).

There were several limitations of the study.  Besides the small size, the main limitation of this retrospective study was a selection bias.  Other limitations included a large number of patients with comorbid conditions and the coincident usage of acid-suppressing medications.  19 of 24 patients had one or more significant comorbid conditions: laryngomalacia in 10, prematurity in 5, genetic syndromes in 3, esophageal atresia in 1, and SLE in 1.

Take-home point: This study is in agreement with the general consensus that GER (acid and non-acid) may trigger sleep interruptions in infants. Nevertheless, given the lack of impact on management, only rarely will infants with poor sleep benefit from these investigations.

Related blog entries:

How Histamine-2 Receptor Blockers May Cause Problems for Preemies

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Previously, this blog has noted an association between ranitidine usage and necrotizing enterocolitis (NEC) (see below).  Now, another study provides insight into a potential mechanism (JPGN 2013; 56: 397-400).

This study examined the fecal microbiota in 76 premature infants who were enrolled in a case-controlled, cross-sectional study.  25 infants receiving H2-blockers were compared with 51 matched controls.

Results: microbial diversity was lower, relative abundance of Proteobacteria was increased, and Firmicutes was decreased in the stools of infants receiving H2-blockers.

While this study did not specifically examine the effect of H-2 blockers on NEC (no infants in this study had NEC), there are multiple reasons why the findings should be a cause for concern.

  • Gastric acidity acts as a natural defense against bacterial growth and H-2 blockers (as well as proton pump inhibitors) inhibit this defense
  • Previous studies have shown an association between NEC and with diminished microbial diversity/increased Proteobacteria.  Proteobacteria include well-known pathogens like Klebsiella, Shigella, Escherichia coli, and Citrobacter.

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Finding the Right Specialist

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A recent clinical problem-solving case report highlights the fact that seeing the right specialist helps a great deal with pattern recognition (NEJM 2013; 368: 1345-51).  In this report, intriguingly titled “The Essential Element” the authors describe a 21-year-old who presented with refractory hemolytic anemia along with low albumin, low alkaline phosphatase, and elevated total & direct bilirubins.  Her course was somewhat protracted due to treatment of hemolytic anemia and lack of recognition of underlying hepatocellular disease.  After readmission three months later the diagnosis of Wilson’s disease was made and quickly she underwent orthotopic liver transplantation.

A couple of pointers from this article for me included the following:

  • Parenchymal injury from the oxidative effect of copper leads to the hepatocellular injury.  Release of copper also causes oxidative damage of erythroctye membranes.
  • The low alkaline phosphatase which is characteristic of Wilson’s is potentially due to the oxidative damage from free radicals or by competition at the active site of the alkaline phosphatase enzyme.
  • The combination of hemolysis with liver dysfunction should prompt consideration of Wilson’s.

Most hepatologists would quickly recognize the pattern presented in this case report.  Getting the patient to the right physician is the key.

Comprehensive review on Wilson’s:

Diagnosis and treatment of Wilson disease: An update – American …  AASLD Guidelines for Wilson disease.  This is an excellent resource for diagnosis and management.