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.

Reliability of colonic manometry

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As noted in a previous blog entry (Gastroesophageal Reflux: I know it when I see it | gutsandgrowth), it is often surprising how variable test result interpretation can be in the hands of experts.  The most recent example of this is with colonic manometry (JPGN 2012; 55: 548-51).

In the current study, 57 colonic motility studies were independently reviewed by 5 experts. The youngest and least experienced was 45 years old with 8 years of experience.  The oldest and most experienced was 63 years old with 28 years of experience.

Unanimous differentiation of normal and abnormal motility studies was present in 69%.  In 81% of the studies, 4 of 5 were in agreement about whether the study was normal.

Specific measurements noted the following:

  • Fairly high degree of agreement with fasting high-amplitude propagating contractions (HAPC): 66% with unanimous agreement,  and 82% with at least 4 of 5 observers in agreement.
  • The gastrocolonic response had the most inconsistency with only 19% in unanimous agreement and 45% with at least 4 of 5 in agreement.
  • The postprandial measurements were reported to be useful in only 3-24% of the studies.

Colonic manometry studies “require interpretation of a complex visual bowel motility pattern and are subject to interpretation bias.” One proposal by the authors of the study would be to limit colon motility studies to 60 minutes followed by bisacodyl stimulation.  Further studies will be necessary to determine whether this will improve the reliability of colonic manometry interpretation.

Related blog entries:

Sedation Safety

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Many parents are terrified of anesthesia and other forms of sedation.  This fear is often not rationale given the excellent safety record.  Given the high publicity though, it is surprising how much variation occurs with regard to monitoring pediatric patients during procedures (Arch Pediatr Adolesc Med 2012; 166: 990-98, editorial 1067-68).  Thanks to Ben Gold for forwarding this article.

In this prospective observational study (2007-2011), 37 U.S. pediatric institutions which comprise the Pediatric Sedation Research Consortium collected data on subjects up to 21 years of age.  In total, data from 114,855 patients were collected.

The most common procedure specialties were radiology (59%), hematology/oncology (14%), and gastroenterology (9%); the most common procedures included MRI, lumbar puncture, bone marrow biopsy, upper endoscopy/colonoscopy, brainstem auditory response test, and catheter placement.

The ASA class were the following: 26% class 1, 56%  class 2, 17% class 3, and <1% class 4 & 5.  The location of procedures were predominantly in either radiology (51%) or sedation unit (43%).

Specific findings:

  • 5% of children did not have pulse oximetry monitoring; this included some ASA 3 and 4 patients.
  • 87% had noninvasive blood pressure monitoring
  • 67% had electrocardiogram (ECG) monitoring; ECG monitoring had the greatest variability in use among various providers
  • Radiologists were the least likely to use any of the measured monitoring modalities.  Pulse oximetry was used in only 33% of procedures in which the radiologist was responsible for sedation; this is compared with >90% of all other providers.
  • 45% were monitored with capnography
  • Guidelines for sedation (AAP, ACEP, ASA) were adhered to for 52% of subjects

While the authors frame the discrepancies as in part due to tailoring the sedation to the individual, they also argue for less variation because patients may have unknown diagnoses and due to iatrogenic error.  Currently, strong evidence-based data on sedation protocols is lacking.  As a consequence, expert opinion guides current practice.

While ECG monitoring had the most variation, it is known to be rarely needed in relatively healthy pediatric populations.  As such, the authors state that ECG monitoring “may be best used in those patients with specific cardiac pathologic features or when a rhythm disturbance is present.”

Use of pulse oximetry should not be overlooked.  Mild hypoxemia has been observed to precede more serious adverse events and may prompt interventions that preclude poor outcomes.

This report has many acknowledged limitations which are common with large database studies.  Nevertheless, the variability in monitoring should help guide ongoing improvement efforts.  While the study also showed very good outcomes (no deaths, one case of cardiac arrest), it is clear that the safety net could be better by making sure each procedure is monitored carefully.  According to AAP guidelines, the minimum consists of continuous pulse oximetry, and intermittent blood pressure monitoring; in addition, capnography (ETCO2) is encouraged.

Learning a lot from ChiLDREN (part 2)

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As noted in previous post (Learning a lot from ChiLDREN (part 1) | gutsandgrowth), several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) has collected prospective longitudinal observational date from multiple centers; data from 10 centers provides useful information on the frequency of portal hypertension (PHT) in young adults with biliary atresia (BA) (JPGN 2012; 55: 57-73).

163 subjects were enrolled between May 2006 and December 2009.  Seven patients were excluded due to the presence of polysplenia which interferes with the assessment of PHT.

Demographics: subjects ranged in age from 1 to 25 years with a mean of 9.2 years.  56% were female, 75% were caucasian.

PHT was considered definite if there was either a history of a PHT complication (variceal bleeding, ascites) or if there were clinical findings c/w PHT (both splenomegaly and thrombocytopenia).  PHT was considered “possible” if either splenomegaly or thrombocytopenia was present and “absent” if no criteria were met.

  • PHT: definite in 80 (49%), possible in 27 (17%) and absent in 56 (34%)
  • 43 subjects had a history of PHT complications: 32 with esophageal variceal (EV) bleeding, 14 with ascites, and 8 with hepatopulmonary syndrome.
  • Of the patients with EV, only 3 had normal platelet count and normal spleen size.

Teaching points:

  1. One-third of subjects with EV bleeding survived with their native liver for at least 5 years.
  2. EV age of onset was highly variable; 7 had bleeding in the first two years of life.
  3. Growth parameters were fairly unremarkable in those with definite PHT.
  4. Long-term followup will be needed to identify factors which predict progression of PHT and the development of adverse outcomes.

Previous related blog posts:

HBV in the Joseon Dynasty

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Investigators have found evidence of Hepatitis B virus (HBV) in the mummified remains of a Korean child from the 16th century (Hepatology 2012; 56: 1671-80).

There are at least 10 HBV genotypes (A-J) and several sub genotypes; each have a specific geographical distribution.  Genotypes are defined by an >8% sequence divergence whereas as sub genotypes have 4-8% sequence divergence.  The HBV in this study corresponds to C2 clade.

While the technical aspects are fascinating, the other important contribution of this article is to the understanding of the evolutionary history of HBV.   There are two theories with regard to the origin of HBV, which may have occurred 100,000 years ago.  One suggests a primate origin with subsequent cross-species transmission.  Another theory suggests a common ancestor of HBV for primates and humans.

In this study, the mummy-derived HBV has the same genotype C which is currently predominant in Korea (>95%); and C2 sub genotype is the most common sub genotype.

The studies conclusions regarding the identification of the subtype is supported by the process of testing the samples in three independent laboratories.  The genetic diversity noted in the sample is likely related to natural evolutionary processes.

Additional references:

Can I take this expired pill?

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While physicians may not be able to recommend the use of expired medicines, it is likely that most drugs remain effective long after the expiration date (Arch Intern Med. 2012;():1-2. doi:10.1001/archinternmed.2012.4501).

In this study, investigators identified eight long-expired medications with 15 active ingredients that were discovered unopened in original containers in a retail pharmacy.  All had expired 28-40 years prior to analysis.

12 of 14 tested drugs retained at least 90% of the labeled amounts.  The authors also note that testing of federal drug stockpiles has shown that 88% of 122 different drugs stored under ideal conditions had their expiration dates extended by more than 1 year (average was 66 months) (Biosecur Bioterror 2009; 7: 101-7).

Given the expense of medications, examining expiration dates would yield significant cost-savings.

Learning a lot from ChiLDREN (part 1)

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Several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In one of these, it is shown that pancreatic insufficiency (PI) is not a common problem for patients with Alagille syndrome (JPGN 2012; 55: 612-614).

In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) collected prospective longitudinal observational date from multiple centers, 16 in this study.

150 subjects who met criteria for Alagille syndrome were enrolled between December 2007 to September 2010.  42 had fecal elastase results available.  Elastase results were characterized as normal if >200 μg/g, indeterminant if 100-200 μg/g, and pancreatic insufficient if <100 μg/g.

  • 40/42 (95%) had normal results
  • 2/40 (5%) were indeterminant

The collaborative study provides a few teaching points:

  1. Fecal elastase is a very reliable tool for detecting exocrine PI with a 99% negative predictive value for ruling out PI.
  2. Previous results suggesting that PI was common in Alagille syndrome were flawed due to the fallibility of previous secretin stimulation testing and due to the occurrence of steatorrhea induced by impaired bile salt secretion

Previous related posts:

Vaniprevir for HCV

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Vaniprevir (MK-7009) is a hepatitis C virus (HCV) NS 3/4A protease inhibitor.  A phase II study has shown that vaniprevir can be an effective agent in combination with pegylated interferon alpha-2a (PEG-IFN) and ribavirin (RBV) (Hepatology 2012; 56: 884-93).

This double-blind, placebo-controlled study examined 94 patients with treatment-naive genotype 1 HCV.  In combination with PEG-IFN/RBV, patients received either placebo, vaniprevir 300 mg BID, 600 mg BID, 600 mg QD or 800 mg QD for 28 days & then open-label PEG-IFN/RBV for 44 weeks.  There were 18-20 patients in each group.

With all of these vaniprevir doses, there was a rapid two-phase decline in viral load; the HCV RNA level was approximately 3log10 IU/mL lower in vaniprevir-treated patients than placebo.  Rapid viral response occurred in 68.8-83.3% of vaniprevir-treated patients compared to 5.6% of control patients.  Sustained virologic response was higher but did not reach statistical significance.

Resistance to vaneprevir with variants at R155 and D168 was detected in a small number of patients.  The authors note that treatment outcomes were not related to interleukin-28B genotype.

The potential advantage of vaneprevir over currently available triple therapy agents (eg. telaprevir and boceprevir) would be easier administration, QD or BID, and possibly more favorable side effect profile.

Take home message: more treatment options, including vaneprevir, for HCV are on the horizon.

Related blog posts:

Testing worm therapy for chronic diarrhea/IBD in Monkeys

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Today’s blog is an excerpt from BBC News (Thanks to Ben Gold for the tip).  The full link:

BBC News – Parasitic worms ‘treat diarrhoea‘

“Chronic diarrhoea could be treated using parasitic worms, a study of monkeys has suggested. Research published in PLOS Pathogens, suggests the treatment restores gut bacteria to a healthy state. Other work in mice has already suggested conditions such as ulcerative colitis could be treated in this way. A UK expert said parasitic worms were being investigated for a range of conditions, including multiple sclerosis and allergies.”

Captivity

“Inflammatory bowel diseases, like colitis, are often fuelled by a wrongly targeted response by the immune system to gut bacteria. Such diseases are more common in developed countries – and scientists suggest this is because people in developing countries have more exposure to parasitic worm (helminth) infections and therefore have a natural protection that has evolved as people and worms learnt to co-exist.


Recent studies have used parasitic worms to successfully treat inflammatory bowel disease in humans, but it is unclear exactly how they do this.

This latest study looked at monkeys because young macaques kept in captivity often develop chronic diarrhoea that can be hard to treat. Five macaques with diarrhoea were treated with parasitic worms called whipworms. Tissue samples were taken before and after treatment and it was found the balance of gut bacteria was restored to required levels. And four out of five animals had less diarrhoea and started to gain weight.

Dr P’ng Loke, of the New York University Langone Medical Center, who led the study, said: ‘The idea for treating colitis with worms is not new, but how this therapy might work remains unclear.  Our findings suggest that exposure to helminths may improve symptoms by restoring the balance to the microbial communities that are attached to the intestinal wall.’

The researchers now plan a study in humans to look at how pig helminth eggs might help alleviate the symptoms of colitis.

Compensating

Prof Graham Rook, of the centre for clinical microbiology at University College London, said a number of research teams were investigating the effects of parasitic worms in various conditions. ‘This is not part of the hygiene hypothesis [which says exposure to bacteria strengthened the immune system]. It’s the “old friends” hypothesis. We co-evolved with these things, so they had to be tolerated. We found ways of suppressing the immune systems, and in some way have come to depend on them.’ And he said the field of research as a whole would be “hugely significant”.  He added: ‘With helminths, if you get the dose right, you can probably live with worms and not have symptoms. But it may well be there is going to be a battery of molecules you could be dosed with to compensate for not meeting our “old friends”.’

THE WONDER OF WORMS

  • Parasitic worms are “old friends” and humans have lived with them for as long as we have existed.
  • And while people in developing countries still do so – and have low levels of inflammatory disease, the opposite is true in developed countries.
  • It appears our immune systems came to rely on parasitic worm infections as part of the way our body defended itself.
  • And when they are no longer there, it appears that may upset our immune systems.
  • Now researchers are looking at how the worms’ effects can be harnessed to treat conditions ranging from multiple sclerosis to allergies.
  • Hookworms and pig whipworms are amongst those being investigated.
  • Results are promising.
  • But those squeamish about dealing with worms or their eggs may not have to worry – it is more likely drugs will be developed that mimic their effects.”

Additional references:

  • -Gastroenterol 2012; 142: 55.  Helminth infection (with enterobiasis) did not reduce risk of IBD in large population-based study (924,000 Danish database).
  • -Gastroenterol 2005; 128: 825. Trichuris suis for UC. 43% improved vs 17% of placebo. Only mildy effective.
  • -Gut 2005; 54: 87-90. Trichuris suis for Crohn’s
  • -Gastroenterol 2005; 129: 768-69. (letter re safety)
  • -NEJM 2010; 363: 1476-78. Interactions between Helminths and immunogenicity.

Missing “C”

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Ascertainment rates for pediatric hepatitis C virus (HCV) are as bad as in adults with HCV (J Pediatr 2012; 161: 915-21).

As noted in previous blog entries, it has been recommended by the CDC that adults born between 1945-65 undergo a one time screening for HCV due to the high frequency of undetected cases along with improvements in therapy.  The same rationale may apply to children in the near future as some of these therapies are shown to be safe and effective in the pediatric population.

In the meanwhile, it is apparent that most pediatric HCV cases remain undetected.  In the aforementioned study, the investigators examined statewide data from Florida and data from health departments across the United States.  This was compared with data from NHANES III which reported HCV prevalence of 0.2% in children 6-12 years old and 0.4% of 13-18 year olds.  The absolute prevalence may be higher as NHANES did not capture some populations at high risk, like homeless or incarcerated youth.

Results:

  • From 2000-2009, only 2007 children were identified as HCV-antibody positive in Florida.  During this period, it is estimated that this represents about 12% of the expected number of cases (n=12155).
  • In Dade county which has 13 pediatric gastroenterologists, 100% responded to an online questionnaire.  They reported caring for 31 cases of HCV in 2009 and another 55 in the preceding 5 years.  This indicates that 1.6% of the expected number of HCV-antibody-positive children in this region received care in 2009 and 2.8% over previous 5 years.
  • Nationwide, only two states (VT, MA) identified more than 20% of expected cases.

Related blog entries:

Mechanisms of irritable bowel syndrome

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An excellent succinct review of the various peripheral mechanisms of irritable bowel syndrome (IBS) has been published (NEJM 2012; 367: 1626-35).  Understanding these mechanisms is crucial in developing and targeting appropriate therapy.

Peripheral factors affecting IBS (Table 1 in review):

  1. Colonic motility –affects up to 45% of diarrhea-predominant IBS and 25% of constipation-predominant IBS.  Specific factors include enteroendocrine cell products (eg. 5-HT, granins), organic acids (eg. bile acids, short chain fatty acids [SCFAs]) impaired bile acid synthesis.
  2. Colonic motor and sensory response to food ingestion. Factors like fat content of meal can contribute to pain, urgency and diarrhea.
  3. Sensing responses in small bowel and colon.  Food stimulation of enteroendocrine cell products may trigger diarrhea, bloating and pain.
  4. Colonic mucosal permeability.  This may lead to malabsorption of carbohydrates or fats and subsequently increased levels of SCFAs.  Also, could trigger immune activation and altered feedback of bile acid synthesis.
  5. Mucosal immune activation.  Previous gastroenteritis along with mast cells, T lymphocytes, and circulating cytokines may be involved factors.
  6. Colonic microbiome.  There may be increased types of some bacteria (eg. firmicutes).  Antibiotics and probiotics could influence the microbiome. Fermentable oligosaccharides, disaccharides, and polyols (FODMAPs) are a group of foods that may trigger IBS symptoms, possibly due to a relationship with the colonic microbiome.

With regard to gluten intolerance, the author notes that the prevalence of celiac disease among IBS is similar to that among controls; however, a subgroup of individuals with diarrhea-predominant IBS respond to a gluten-free diet.

Some genetic factors have been identified which can contribute to IBS:

  • mutation in the guanylate cyclase C secretory pathway
  • mutations that increase the risk of postinfectious IBS
  • genetic variability in bile acid synthesis
  • variation in expression of neurotransmitters and cytokines

Towards the end of the review, the author notes that “IBS is no longer regarded as an idiopathic bowel dysfunction” due to stress.  The specific factors that have been identified will likely be further defined and likely lead to more specific individualized therapy.  Potential treatments:

  • diets -including gluten-free and FODMAPs
  • bile acid sequestrants and 5-HT3 antagonists
  • prokinetics or secretagogues in patients with constipation-predominant IBS
  • probiotics and non-absorbed antibiotics
  • antiinflammatory agents
  • tignt-junction modifiers
  • biofeedback

Previous related blog entries:

Additional references:
  • -J Pediatr 2009; 155: 416.  n=43 children & 56 control pts.  High incidence of abnormal lactulose (65%) breath test with IBS but not control pts (7%).  (lactulose 10g given in 20mL)
  • -Gastroenterol 2009; 137: 766.  Notes relatively weak data supporting use of antispasmotics, probiotics, and antidepressants for IBS.
  • -Am J Gastroenterol 2010; 105: 859-865.  n=466 & 451 controls.  IBS pts with lower incidence of adenomas (7.7.% vs 26%).  9% had diverticulosis (lower).  Microscopic colitis present in 1.5%.
  • -Gastroenterol 2002; 123: 2105-07. & 2108-2131. AGA guidelines for IBS
  • -Gastroenterol 2007; 133: 799.  Natural hx of functional disorders: 20% persist w same Sx, 40% develop other Sx, 40% get better.  Large study from Olmstead county (n=1365)
    • -Clin Gastro & Hep 2005; 3: 397.  managing pts c severe IBS; advocates low dose tricyclics..
  • -Am J Gastro 2003; 98: 412-9.  use of neomycin for SBBO in IBS (43% response). 84% IBS pts c abnl lactulose vs 20% placebo
  • -Gastroenterol 2003; 124: S1152.  only 4 of 33 IBS pts had abnl jejunal samples
  • -J Musculoskel Pain 2001; 9:107-113.  78% of fibromyalgia pts c abnl BHT.