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.

Update for Peutz-Jegher Syndrome

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A recent case series provides some useful insight into this rare condition (JPGN 2013; 56: 191-95).  Peutz-Jegher syndrome (JPS) has an incidence between 1 in 8500 to 1 in 120,000.  It is caused by a germline mutation in the STK11 gene.  It is associated with a serine threonine kinase that functions as a tumor suppressor.

14 children were identified through a medical records review at the Children’s Hospital Colorado between 2000-2011.  Inclusion required 2 or more of the following criteria:

  • 2 or more characteristic hamartomatous polyps of the small intestine
  • typical mucocutaneous pigmentation
  • positive family history (absent in about 25% of cases historically)

Results: Median age at first clinical evaluation was 4.5 years.  Intussusception was noted 7 times in 5 children (ages 5 to 16 years). Surgical reduction was required in 5 of the events. Polyps were found in the stomach/duodenum in 5 (36%), small bowel in 7 (50%), and colon in 3 (21%). Sertoli cell tumors was identified in 2 of the 10 boys at ages 8 years and 11 years.

Based on their experience, the authors suggest the following:

  • Initial screening start at age 4-5 years of age.  They recommend capsule endoscopy, upper endoscopy, and colonoscopy (CE/EGD/colon) as initial screen.  Then, they suggest repeating every 1-2 years until no polyps and then every 2-3 years.
  • In boys, they recommend breast exams for gynecomastia and testicular exams annually to screen for Sertoli cell tumor.  In girls, monitoring for precocious puberty and if present, then further evaluation for Sertoli cell tumor.

Given the small size of their cohort and the likelihood that asymptomatic children may not have been seen, it is too early to know if the approach recommended by the authors is justified.  Will earlier screening result in any long-term benefit &/or reduce complications related to JPS?

SFED works for EoE!

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A recent study confirms that an empiric ‘6-food elimination diet’ (SFED) works in adults  with eosinophilic esophagitis (EoE) as well as it has been shown to work in kids (J Allergy Clin Immunol 2013; 131: 797-804)).  Thanks to Seth Marcus for this reference.

This Spanish study recruited 67 consecutive adult patients (17-60 years) who were treated with an exclusive diet which eliminated milk (avoided goat’s milk too), wheat/cereals (avoided rice and corn too), eggs, fish/seafood, legumes/peanuts, and soy for 6 weeks.  Subsequent rechallenge followed with repeated endoscopies every 6 weeks.  A food was considered a trigger for EoE if eosinophilic infiltrate ≥ 15 Eos/hpf after reintroduction.

Prior to reintroduction, 73% (n=49) responded to SFED with peak Eos < 15/hpf. Among responders, 37 patients achieved a complete response with Eos 0-5/hpf.  Subsquently rechallenges were instituted and 42 patients completed this part of the study. A single food was identified in 36%, 2 food triggers in 31%, the remainder had at least 3 food triggers.  Cow’s milk was the most common food trigger, in 62%, followed by wheat (29%), eggs (26%), and legumes (24%).

Allergy testing (ImmunoCap IgE-based testing, and skin prick testing) showed no concordance with food reintroduction challenge results.  All patients maintained on avoidance of offending foods maintained remission for up to 3 years.

In the general scheme of food reintroduction, it is interesting that the authors often tested for wheat and milk first.  Also, the Table 1 listed numerous characteristics of responders and nonresponders and none of these had a significant predictive effect.  This table listed symptoms including dysphagia, vomiting and pain, caliber of esophagus, mucosal appearance, atopic history, atopic family history, and eosinophil counts.

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Off-label medications in pediatrics

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In the U.S., multiple legislative changes have been improving the information available for off-label use of medications (JPGN 2013; 56: 113-4).

The Pediatric Research Equity Act (PL 108-155) and the Best Pharmaceuticals for Children Act (PL 107-109) help the Food and Drug Administration (FDA) promote pediatric trials and better information.

  • Pediatric data must be included in labeling whether results are positive, negative or inconclusive
  • If pediatric trials are not completed because the drug would be ineffective or unsafe, this information must go into labeling
  • Public internet posting of certain FDA pediatric reviews is required regardless of whether the trials led to an approval

Despite these improvements, the data may be difficult to interpret.  The authors of this commentary note that only “48% of trials of products that had pediatric safety information added to the product’s labeling were reported in the peer-reviewed literature.”  Furthermore, in about half of the published articles, the studies did not emphasize the same information as the FDA labeling.

Even when a fair amount of data is provided, it is frequently ignored.  A specific example given by the authors: lansoprazole. Lansoprazole is not approved in patients younger than 1 year and labeling describes a negative trial in this age group. Yet, in the U.S., lansoprazole was dispensed off-label in this population approximately 358,000 times in 2010.

Pharmaceutical companies benefit whether the prescription is for an approved indication or for an off-label use.  Even with approved uses, there have been substantial concerns about adverse effects.  The likelihood of more risk and less benefit is much greater for off-label use.

So with the next prescription, it might be worth thinking about whether the medication works, whether there is sufficient data to support an approved indication, and how much risk is involved.

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Mortality from IBD

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A large Danish cohort provides useful information on the mortality effects of having inflammatory bowel disease (IBD) and how this has changed over the last three decades (Clin Gastroenterol Hepatol 2013; 11: 43-48).

Using a national cohort of all individuals living in Denmark between 1982-2010 (on average 5.3 million), the authors studied 36,080 patients with ulcerative colitis (UC) and 15,361 with Crohn’s disease (CD) in comparison to data from 2,858,096 matched controls (50 controls from each IBD patient) from the general population.  For UC, the median age was 45.2 years and for CD 36.3 years.

Findings:

  • With UC, the first year of diagnosis carried a higher risk of dying (HR 2.43) then rapidly declined to around HR 1.1 after 2 years.  Overall, long-term mortality was increased 10% among UC patients.  Mortality from UC decreased from 1982 to 2010 due to decreased mortalities from gastrointestinal disorders, including colorectal cancer.
  • Mortality was higher among patients diagnosed at younger ages.  Patients diagnosed with UC in childhood or adolescence had a 2.15-fold higher relative mortality than patients diagnosed with UC at 60-79 years.
  • Cause-Specific Mortality: during the first year after UC diagnosis, the HR ratio was increased markedly for gastrointestinal disease (HR 13.3) and infection (HR 9.17).  These areas were most prominent at 10+ years, but the HR ratios had decreased to 1.95 and 1.64 respectively at that time.
  • For CD, mortality was markedly increased in the first year with HR 3.69 and declined to HR 1.53 during years 2-4; HR was 1.49 at 10+ years following diagnosis.  Overall, long-term mortality was increased 50% among CD patients.  Unlike UC, no improvement in mortality rate occurred during the study.
  • Cause-Specific Mortality: during the first year after CD diagnosis, the HR ratio was increased markedly for gastrointestinal disease (HR 23.02) and infection (HR 10.19). These areas were most prominent at 10+ years, but the HR ratios had decreased to 3.67 and 2.70 respectively at that time.  Infections were not increased in the most recent decade, indicating that thiopurines and biologics have not increased the overall risk of fatal infections.
  • While the relative risk of cardiovascular disease was only slightly increased (HR 1.11 for both CD and UC), this is important given the overall frequency of cardiovascular disease in the population.  Presumably, systemic inflammation contributes to the formation of atherosclerosis.
  • Suicide was also increased, especially in the first year after diagnosis (HR 2.05 for UC and HR 1.37 for CD)

Strengths of study: since Denmark has free access to health care and all citizens have a unique 10-digit personal identification, this enables capture of virtually all patients with IBD.  Previous studies have validated the database to be accurate and that the IBD diagnoses have been validated.

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Gut microbiome and endogenous alcohol

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At first glance, it sounds like an ambitious project -develop a gut microbiome that produces alcohol.  It could obviate the need for “Duff” beer (Duff Beer – Wikipedia, the free encyclopedia).  Yet, a recent article has found that an altered microbiome with increased endogenous alcohol already exists and it is associated with nonalcoholic steatohepatitis (NASH) (Hepatology 2013; 57: 601-609).

In this study, the authors examined three pediatric populations: a healthy control group (n=16), obese group (n=25), and NASH group (n=22).  All NASH patients had undergone liver biopsy and met Kleiner’s criteria; in contrast, the obese group had normal LFTs.

Key study findings:

1. The microbiome from the obese and NASH patients were similar but had some striking differences compared with the control group patients (pie chart –Figure 2):

  • Bacteroidetes (including Bacteroides): 28.65% in healthy controls, 50.28% in obese, and 49.11% in NASH
  • Firmicutes (including Blautia and Faecalibacterium): 66.78% in healthy controls, 42.62% in obese, and 42.39% in NASH
  • Proteobacteria (including Escherichia): 0.87% in healthy controls, 3.13% in obese, and 6.03% in NASH

2. Elevated serum ethanol concentrations only in NASH population: ~26 μM in both control and obese groups compared with ~35 μM in NASH patients.

Under normal conditions, endogenous alcohol is produced in the human body and the intestinal microflora are the major source.  This gut-produced alcohol is quickly metabolized by the liver.  Due to similar histology between NASH patients and patients with alcoholic liver disease, it has been hypothesized that NASH patients may have elevated blood alcohol.  This study adds further evidence to this hypothesis and provides a potential mechanism; namely, increased bacteria like Escherichia and Bacteroides can increase endogenously-produced alcohol.

Will efforts to revert the microbiome to normal have therapeutic effects on NASH?  This important question will need to be addressed given the growing problem of fatty liver disease.

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Cognitive Behavioral Therapy for Childhood Abdominal Pain

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Cognitive behavioral therapy (CBT) can be effective for children with functional abdominal pain (JAMA Pediatr 2013; 167: 178-84).  Thanks to Ben Gold for this reference.

This prospective, randomized study recruited 200 children and their parents.  One group of child-parent dyads received ‘social learning and cognitive behavioral therapy’ (SLCBT) and the other group ‘education and support’ (ES).  Over the course of a year, children in the SLCBT group reported greater baseline decreases in gastrointestinal symptom severity and better pain-coping responses.  Parents in the SLCBT group reported greater decreases in ‘solicitous responses’ to their child’s symptoms along with decrease in maladaptive beliefs regarding their child’s pain.

The intervention in the SLCBT group was three 1-hour sessions approximately 1 week apart in which parents were taught social learning strategies 1) to reduce ‘solicitous responses’ to illness behavior, and 2) to model /reinforce healthier ways to respond to gastrointestinal discomfort.  Then, assessments were made at 1 week, 3 months, 6 months, and 12 months.

This study shows that CBT can be effective for functional abdominal pain, if you can find skilled therapist and families willing to participate.

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Stopping reflux with magnets

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Gastroesophageal reflux disease (GERD) can be treated by bolstering the lower esophageal sphincter with a surgically-implanted bracelet of powerful magnets (NEJM 2013; 368: 719-27).

In a prospective study, 100 patients with GERD were enrolled in this study.  The study was conducted in 13 centers in the U.S. and 1 in the Netherlands.  It was designed by Torax Medical.  There was no control group. The primary outcome was normalization of esophageal acid exposure or a 50% greater reduction in exposure at 1 year.

Patient selection:

  • Inclusion criteria: 18-75 years with at least 6-month history of GERD and partial response to proton pump inhibitor treatment.  All patients had to have abnormal pH probe studies at baseline.
  • Exclusion criteria: large hiatal hernia, grade C or D esophagitis (Los Angeles classification), BMI >35, Barrett’s esophagus, motility disorder, dysphagia more than three times a week, or allergy to implant components.

Results:

  • Primary outcome was achieved in 64% of patients.
  • Secondary outcomes: a reduction of proton-pump inhibitor (PPI) use of 50% or more was achieved in 93%.  In fact, at 3 years, 87% had completely eliminated the use of PPIs. Quality of life scores improved in 92%.
  • Adverse effects: most common was dysphagia (68% postop, 11% at 1 year, 4% at 3 years).  This often resolved after esophageal dilatation.
  • Six patients had the device removed.

The bracelet of beads contained sealed magnetic neodymium iron boride.  Each bead is connected by a small wire to the next.  The small wires allow for expansion of the bracelet. It is also designed to avoid compression of the esophagus as the beads can rest against each other.  In addition, the beads separate with the transport of food or if increased intragastric pressure (eg. belch or vomit).

The median time for the procedure of laparascopic placement was 36 minutes. This study brings the worldwide clinical experience to 497 magnetic implants.  To date, there have been no reported erosions or migrations.

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Heart-healthy Mediterranean Diet

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From AJC (see link below): “The study lasted five years and involved about 7,500 people in Spain. Those who ate Mediterranean-style with lots of olive oil or nuts had a 30 percent lower risk of major cardiovascular problems compared to those who were told to follow a low-fat diet but who in reality, didn’t cut fat very much. Mediterranean meant lots of fruit, fish, chicken, beans, tomato sauce, salads, and wine and little baked goods and pastries.” Methods (at NEJM.org) “In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years.”

Related blog entry: Six years later-Mediterranean diet comes out on top | gutsandgrowth

FMT -fecal microbiota transplant

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An excellent review of FMT, especially in regard to C difficile infection, has been published (Am J Gastroenterol 2013; 108: 177-85)  Thanks to Ben Gold for sharing this reference.

FMT has been around for a long time.  It is first documented in the 4th century as a treatment for food poisoning or severe diarrhea.  Its current application has focused on C difficile infection (CDI), though its use in a number of other settings is being explored.  This includes irritable bowel syndrome and inflammatory bowel disease.

This articles makes several useful points.  In the ‘how to do it’ section, the author notes that at the NIH, donor screening includes screening for pathogens in the stool:

  • Bacteria: C difficile, Listeria monocytogenes, Vibrio cholera, Vibrio parahemoltyicus, H pylori
  • Parasites: Giardia, Cryptosporidium, Isospora (acid fast stain)
  • Viruses: Rotavirus
  • Blood: for Hepatitis A IgM, Hep B (HBsAg, anti-HBc ([gG & IgM]), HIV, Syphilis, HCV

However, the author notes that testing in the community tends to rely on screening only for enteric pathogens (stool tests only).  Donors should be excluded if they have received antibiotics in the preceding 3 months, if they participate in high-risk sexual behaviors, recent tattoo piercing, or recent incarceration.  Additional exclusions: history of IBD, IBS, immunocompromise, morbid obesity, metabolic syndrome, atopy, and chronic fatigue.

Related donors may provide a better long-term outcome.  In a recent review, FMT using a related donor yielded a 93% CDI resolution compared with 84% for unrelated donors.

Nuts and bolts:

  1. Donor is instructed to take a double dose of milk of magnesia at bedtime the night before procedure.
  2. Soft stool is passed into a clean plastic container; preference is for stool to be produced within 8 hour of FMT.  Stool does not need to be frozen or refrigerated (though can be refrigerated).
  3. Saline is added to the stool which is stirred and shaken (some use blenders, some use milk or water as suspending solutions).
  4. Typical amount of stool would be 50 g in 250 cc diluent.  For colonic administration, about 300 cc are administered in cecal region.  For duodenal administration, about 60 cc are administered.
  5. Prior to administration, it is best to filter the mixture through gauze pads to remove particulate matter that would interfere with administration.
  6. Though the author notes that there have been recommendations to prepare stool under a hood as stool is considered a level 2 biohazard, he states that this is not practical and in fact, the stool in this situation is the safest stool that gastroenterologists encounter.
  7. Recipients receive a colon lavage before the procedure regardless of route of FMT administration. If possible, all antibiotics are withheld 3 days prior.
  8. On the morning of administration, the author instructs recipient to take two lopermide tablets.

As positive experience gains in CDI, further efforts in a number of other diseases (>30 listed in Table 1 of article) with altered microbiome will be explored.  Thus far, FMT has been used in autism, fibromyalgia, metabolic syndrome, multiple sclerosis, obesity, and even parkinson’s disease.

Hippocrates stated “All disease begins in the gut.”  Given the diversity of diseases in which FMT is being examined, this sentiment may be close to the truth.

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Pediatric NAFLD histology score

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Pathologists may be more interested in this article than many pediatric gastroenterologists (J Hepatol 2012; 57: 1312-18).  Yet, the development of the pediatric NAFLD (non-alcoholic fatty liver disease) histological score (PNHS) is likely to be helpful, particularly in research of NAFLD.

In this study, an initial training set of 203 children with biopsy-proven NAFLD were examined.  After designing a scoring system, the PNHS was validated in another 100 children.  The mean age was 12.4 years.

PNHS = 100 x esp(Zphs)/[1 + exp(Zphs)]

Zphns = -8.4 + (2.5 x steatosis) + (3.5 x ballooning) + (3.4 x lobular inflammation) + (0.87 x portal inflammation)

This score is easily calculated by entering the individual histological features at the following website:

  • steatosis 1-3 (1=5%-33%, 2=34%-65%, 3=≥66%)
  • ballooning 0-2 (0=none, 1=few, 2=many)
  • lobular inflammation 0-3 (0=none, 1=<2 under 20x, 2=2-4 under 20x, 3=>4 under 20x)
  • portal inflammation 0-2 (0=none, 1=mild, 2=more than mild)
  • http://rcc.simpal.com/RCEval.cgi?RCID=RPCxtv#Result

Results:

  • In NASH patients, the mean PNHS was 89 ± 20.5 compared to 21.9 ± 24.5 in the non NASH patients.
  • There was a high level of agreement between categorization of NAFLD cases using PNHS compared with pathologist diagnosis.
  • NASH patients were much more likely to have metabolic syndrome (64%) compared with 38% for non-NASH patients
  • Of the histologic features, ballooning was the feature that most distinguished the cohorts.  In 66% of NASH patients, few or many ballooning hepatocytes were noted, whereas 96% of non-NASH patients had no ballooning noted.
  • With PNHS of ≥85, the sensitivity is 76-77% and the specificity is 91-97% for NASH.  This will decrease the number of ‘borderline NASH’ cases in pediatric cohorts.

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