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.

Chronic Care Mode: GJ tube Data

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A lot has changed in the field of pediatric gastroenterology since I completed my training 16 years ago.  One technology that is used frequently now is the gastrojejunal (GJ) tube for feeding neurologically-impaired children.  Previously, GJ tubes were used as a temporary solution.  Part of the rational for short-term usage was that these tubes were often difficult to maintain; they could easily become dislodged or clogged.

A recent study documents the more frequent usage of GJ tubes and their indefinite usage to treat complex feeding issues (JPGN 2013; 56: 523-27).

This retrospective chart review encompassed a 10 year period (1999-2009) at a single academic center.  In total 33 patients were treated with GJ tubes with 160 placements.  The mean age at initial placement was 6 years and the mean weight 19.4 kg. 76% of the patients had cerebral palsy/neurologic disorder, 21% had congenital heart disease, and 9% had chronic lung disease.

Common indications for replacement: dislodgment, obstruction, coiling into stomach, and broken tubing.

Three techniques were used:

  1. Fluoroscopy with guide wire and subsequent GJ
  2. Gastroduodenscopy via gastrostomy site to place guidewire for GJ placement
  3. Tube placement during esophagogastroduodenoscopy

Most procedures (85%) did not require sedation.

Outcomes:

  • 13 (39%) maintained on GJ throughout study period
  • 10 (30%) converted to gastric or oral feeds
  • 5 (15%) surgical intervention
  • 5 (15%) deceased
  • Duration of tube survival: mean 91 days for Mic-Key GJ (low profile) and 177 days for  coaxial PEG-PEJ (e.g. 16 French Corflo gastric tube with 6 French jejunal tube)

When reading the study, it is hard to ignore Figure 3 which shows more than 30 placements per year after 2007 whereas the number was about two per year before 2001. In the discussion, the authors do not focus on how this technology has been embraced so widely.  It is mostly a discussion on the indications, methods, and complications.  Indications included high aspiration risk, intractable vomiting, failed Nissen fundoplication, and gastroparesis.  “Our study showed that long-term jejunal feeding via GJ tubes is possible and safe.”

My preference is generally to avoid GJ feedings as a primary intervention for long-term feeding problems.  That is, when patients need gastrostomy tube feeds but are prone to vomiting, most often a fundoplication is worthwhile.  When a patient has had a fundoplication that is no longer effective, a GJ tube should be considered.

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Spina Bifida, Humility, and Quality of Life

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While a recent article (J Pediatr 2013; 162: 993-98) on spina bifida and its effect on quality of life provide useful information, the accompanying editorial by John Freeman (J Pediatr 2013; 162: 894-95) had much broader implications for me.

The referenced article provides data showing the effects of spina bifida on quality of life QOL), even in those who reported their current health as good.  The tools that the investigators used for 40 youth and 13 young adults were the HUI-3 and AQoL.  Both of these tools correlated health-related QOL (HR-QOL) and the level of the anatomic lesion; those with thoracic/higher lesions had worse HR-QOL.

Some of the points made by Dr. Freeman:

  • Quote at start: “Health: A state of complete physical, mental, and social well-being and not just the absence of sickness or frailty.” –World Health Organization
  • In 2004, he followed up with two patients who he had presumed to be quite successful.  Both “were living at home, wheelchair-bound, with high paraplegias.  Both were community college graduates and employed….When I asked them what I should tell parents delivering a newborn with spina bifida, each replied, ‘I wish I had never been born.’ I was shocked.”
  • He notes that the referenced article had a low participation rate (39%) which could introduce significant biases.  “Were the respondents those with greater or less disability?”
  • Conclusion: “I will not presume to have answers to these questions but propose further discussion of the quality-of-life issues…on decisions regarding early treatment of spina bifida.”

These studies make it clear that some children with spina bifida, particularly those with higher lesions, have poor HR-QOL.  The broader implication is that many children/adults who we think are doing pretty well do not see it that way.  Trying to determine what the future holds for children with chronic health problems in infancy is difficult.  Even in the most severe diseases, most parents want everything done.  Will this type of information change anything?

An easy tool to assess cardiometabolic risk

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There are a large number of anthropometrics to assess nutrition; however, simplifying the assessment would facilitate broader usage.  To that end, a recent publication suggests that checking triglyceride level and waist circumference is helpful to identify cardiometabolic risk (J Pediatr 2013; 162: 746-52).

This study used a cross-sectional design; anthropometrics, biochemistries, and cardiorespiratory fitness were assessed in 234 participants between 10-19 years of age.

Specific measurements included the following: weight, height, waist-to-height ratio (WHTR), lipid panel, blood pressure, and a cardiorespiratory fitness (CRF) as assessed by a progressive cycle ergometer tests.  The authors defined a HW or hypertriglyceridemic waist phenotype characterized as having a triglyceride ≥110 mg/dL and a waist circumference ≥ 90% for age/sex.

Key findings:

  • Participants with the HW phenotype were unlikely to have a high CRF (OR 0.045).  In addition, they had a high likelihood of elevated LDL (OR 4.41), impaired fasting blood glucose (OR 3.37).
  • Those with high WHTR were at higher odds for having low HDL (OR 2.57), high diastolic BP (OR 3.21) compared with normal WHTR participants.

From theory to bedside practice

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“That’s fine in practice, but how does it work in theory?”

I heard this quote while visiting the University of Chicago. A recent (really cool) study reminded me of this quote because of the interplay between predictions of the effects of a genetic defect in bile acid conjugation and the actual clinical presentation of 10 pediatric patients  (Gastroenterol 2013; 144: 945-55).

Background: Bile acid synthesis from cholesterol requires 17 enzymatic reactions in different cellular compartments of the hepatocyte.  These steps are tightly regulated.  All of the steps are vulnerable to genetic defects, some of which have been recognized for a long time.  The final step occurs in the peroxisome and is 2-part mediated by bile acid-CoA ligase enzyme (SLC27A5) and bile acid-CoA:amino acid N-acyltransferase (BAAT). This latest study examines the final step of primary bile acid synthesis in which there is conjugation with amino acids. Conjugation of bile acids improves absorption of lipids including fat-soluble vitamins.

Results: Ten patients with severe fat-soluble vitamin deficiency (five with rickets) were carefully analyzed. Levels of urinary bile acids showed increased unconjugated forms (79%).  In addition, there was an absence of glycine and taurine conjugates in the urine, bile, and serum. In the 8 patients with duodenal bile analysis, >95% of bile acids were unconjugated which was too low for efficient lipid absorption. Typically, glycine and taurine conjugates account for >95% of bile acids secreted in bile.  On mass spectrometry, there was a marked presence of a dominant ion at m/z 407 which represents cholic acid.  The investigators also performed molecular analysis and identified mutations in BAAT in 7 of 8 who had available DNA.

Clinical features:

  • Hepatomegaly in 3 of 10
  • Age at diagnosis: 3mo-14 years
  • Elevated aminotransferase: 4 of 10
  • Low GGT
  • Liver failure/transplant in one patient
  • All 10 had fat-soluble vitamin deficiency
  • None had diarrhea (which had been theorized)

Thus, patients had variable liver disease ranging from none to severe.

Take-home message(s):

Specific genetic defects have been identified in the final steps of bile acid production. Abnormal urine mass spectrometry may increase the suspicion for mutations in BAAT (or SLC27A5).  Breakdown in any of these bile acid synthesis steps can lead to fat-soluble vitamin deficiency.  Potential treatment with primary conjugated bile acids (e.g.. glycocholic acid) should improve fat-soluble vitamin absorption in these patients.

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Why Eliminating Gluten May Help Irritable Bowel Syndrome

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As noted in previous posts, gluten-free diets (GFDs) have become commonplace for individuals without celiac disease.  Clinically, subgroups of patients with irritable bowel syndrome (IBS) were noted to have gluten sensitivity.  But, these subgroups were difficult to define and the mechanisms of improvement with a GFD were purely speculative.  A new study identifies changes in the frequency of bowel habits and mucosal permeability associated with a GFD among diarrhea-predominant IBS patients (Gastroenterol 2013; 144: 903-11).

While the investigators conducted a trial of short duration (4 weeks) and only enrolled 45 patients, they completed a number of sophisticated studies.

Design: 45 patients were randomized into either a gluten-containing diet (GCD, n=22) or GFD (n=23).  In each group, there were 11 patients who were HLA-DQ2/8 positive.

Measurements:

  • Daily bowel frequency
  • Small bowel and colonic transit
  • Mucosal permeability using lactulose/mannitol excretion.  Lactulose is normally not absorbed except with increased permeability. Mannitol is passively absorbed throughout intestine.  Higher lactulose:mannitol ratio in urine reflects intestinal permeability.
  • Cytokine production
  • Rectosigmoid biopsies (from 28 patients) to analyze messenger RNA for tight junction proteins and immunohistochemical staining

Key Results:

  • Fewer bowel habits were noted in patients receiving GFD.  In this group, bowel habits decreased from ~2.6/day to 2/day.  This was significant compared with GCD group.  Furthermore, this effect was more pronounced among patients positive for HLA-DQ2 or HLA-DQ8.
  • There was no significant change in stool form or ease of passage between GFD and GCD groups.
  • GCD had increased small bowel permeability as shown by mannitol excretion and lactulose-to-mannitol ratio (specific #s Table 1). Again, this effect was more pronounced among patients positive for HLA-DQ2 or HLA-DQ8.
  • GCD group had a reduced mRNA expression of mucosal tight junction proteins.
  • GCD was not associated with significant effects on colonic transit, immunocyte activation, or altered histology (eg. increased intraepithelial lymphocytes, change in crypt:villus ratio).

The increased changes in HLA-DQ2/HLA-DQ8 suggest a role for adaptive immune response in mediating GCD effects on barrier function.

Conclusion: “our data provide mechanistic explanations for the observation that gluten withdrawal may improve patient symptoms in IBS.”

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Microtargeting HCV

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“Where there is no vision, the people perish.” –King Solomon, Proverbs

A recent study (NEJM 2013; 368: 1685-94) sheds light on a new vision of potential therapies, using microRNAs designed to interfere with the pathogenesis intracellularly.  While this study used this technology to target the Hepatitis C virus (HCV), the same technology has already received FDA approval for a medication (mipomersen) used to treat familial hypercholesterolemia.

With familial hypercholesterolemia, antisense oligonucleotides were developed which inhibit the expression of apolipoprotein B-100 in the liver.  For HCV, miravirsen is a 15-nucleotide antisense oligonucleotide microRNA (miR-122) which binds two highly conserved sites in HCV RNA.  The liver-expressed miR-122 protects HCV from degradation. Thus, the antisense oligonucleotide miravirsen causes degradation of HCV.  All strains of HCV depend on miR-122. (This aspect is reiterated in an associated editorial: NEJM 2013; 368: 1741-43.)

This study enrolled 36 patients from 2010 to 2011 in a randomized, double-blind, placebo-controlled, sequential series, ascending multiple dose-ranging study (7 study sites).  All HCV patients had not received previous therapy and were genotype 1.  Patients received five weekly subcutaneous injections of miravirsen at 3 mg/kg, 5 mg/kg, 7 mg/kg or placebo injections.

Results: In the miravirsen groups, the mean maximum log reduction in HCV RNA level was related to dose: 1.2 in 3 mg/kg cohort, 2.9 in 5 mg/kg cohort, and 3.0 in 7 mg/kg cohort compared with a 0.4 reduction in the placebo cohort.  During 14 weeks of follow-up after completing treatment, HCV RNA was not detected in one patient in the 5 mg/kg group and in four patients in the 7 mg/kg group.

There were no dose-limiting toxic effects or treatment discontinuations because of adverse events.  However, cholesterol levels did decrease by ~25%. No viral resistance was identified.  In addition, during treatment with miravirsen, a sustained decrease in serum alanine aminotransferase was evident.

The authors note that the pharmacologic data from this study indicate that once-monthly regimen would be feasible.  Because miravirsen is not a substrate for P-450, it is not expected to have significant drug-drug interactions.  Further studies are underway.

Potential drawbacks of treatment: miR-122 is a tumor-suppressor gene for hepatocellular carcinoma (HCC).  Thus, treatment with miravirsen could increase the risk of HCC.  Also, in mice that lack miR-122, there is a high risk of fatty liver and fibrosis.

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Therapeutic Misadventures with Acetaminophen

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I first heard the title expression “Therapeutic Misadventure” from one of my mentors, Jim Heubi (J Pediatr 1998; 132: 22-27), though he did not coin the term.  As a personal aside, Jim interviewed me prior to my pediatric residency and helped convince me to train in Cincinnati.

Some have said the phrase is a ‘nice medical term for a mistake.’  A more precise definition: “therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease” (from the following link: Therapeutic misadventure).

The latest data on therapeutic misadventures with acetaminophen has emerged in a recent report: Pediatrics 2013; 131; e740-e746.

This observational cohort study analyzed a group of 666 children from 22 sites who were enrolled in the Pediatric Acute Liver Failure (PALF) study.  The children were subdivided based on acetaminophen (N-acetyl-p-aminophenol [APAP]) exposure: 85 with single toxic dose exposure (SE), 83 with chronic exposure (CE) ≥ 2 doses, and 498 with no exposure.

Among the CE group, 22% were assigned a final diagnosis of APAP toxicity; the majority in the CE group had 3 to 7 days of exposure to APAP.  The median dose was 31 mg/kg/day. Only 31 CE patients had serum APAP levels performed; in this group, a similar proportion to SE patients had elevated APAP levels ≥10 mg/L (68% in CE and 66% in SE).   Besides APAP toxicity, final diagnosis included indeterminate in 31 (37%), autoimmune (7%), metabolic (5%), infection (8%), and other (21%).

Among the SE group, 82 (96.5%) had APAP overdose as final diagnosis and 3 (3.5%) as indeterminate.

Among the NE group, 234 (47%) had a final diagnosis of indeterminate; other diagnosis in the remaining: infection 51 (10.2%), metabolic 72 (14.5%), autoimmune 34 (6.8 %), and other 107 (21.5%)

Clinical outcomes: 21 days after enrollment, 68% of CE patients were alive without liver transplantation; this compared with 92% of SE patients and 48% of NE patients.  In both the CE and NE patients, there was a high percentage of patients with indeterminate etiology.  Indeterminate ALF is associated with increased risk of liver transplantation and death.

Conclusions from the authors: a low serum bilirubin and high ALT should raise suspicion for CE to APAP.  CE patients outcomes were not as favorable as SE patients.  Better communication between physicians and families about the risk of prolonged use of APAP is needed.

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“Family Feud” for Pediatric Crohn’s Abscess Management

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Initially, this blog entry was titled “What is the best way to manage an intra-abdominal abscess in pediatric Crohn’s disease?”  My answer was simple: it depends on who you ask (Inflamm Bowel Dis 2013; 818-25).  As I thought about this study, the responses reminded me of “Family Feud” minus Richard Dawson.

This survey examined the responses of NASPGHAN members.  Of the initial 1608 emails which were delivered, 248 fully completed surveys.  25% of respondents were in practice for >20 years and 26% treated >50 patients with Crohn’s disease (CD). 87% of respondents were from U.S.

  • What is the best way to image initially?  52% recommended CT scan, 26% MRI, and 21% ultrasound.
  • What is the best modality for followup imaging? 47% ultrasound, 33% MRI, and 13% CT
  • Antibiotics or drainage for abscess <2 cm? 61% recommended antibiotics; 51% would treat for 3-4 weeks, whereas 19% for 1-2 weeks.
  • Antibiotics or drainage for abscess >2 cm? 28% would attempt antibiotics alone
  • When is surgery indicated? 75% said only in select cases after completing antibiotics and interventional radiology drainage.
  • Anti-TNFα therapy?  The survey also questioned the shortest preoperative interval one would prescribe anti-TNFα therapy.  The results ranged from 12% for <1 week to 45% who would not give anti-TNFα therapy at all.

The authors note that there is “a paucity of research and practice guidelines for the optimal management of children with intra-abdominal abscess.”  There were no trends in management identified based on practitioner level of experience.  Some answers to the questions are alluded to by the authors but not expressed definitively. For example, “several studies have reported a lack of association between infliximab and an increased rate of postoperative complications.” “Most infections that occur while on anti-TNFα therapy tend to be opportunistic, not bacterial.”

The study’s conclusions are limited by the low participation rate.  In addition, when physicians are confronted with a specific situation, their response in practice may be different than in a theoretical scenario.  However, it appears that the answers to these important questions are closer to guesses on a game show rather than best care.  More research and collaboration is needed to reduce this highly variable care and determine the most effective approach.

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The Paradox of Vaccine Resistance

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A recent editorial highlights the fact that the “last mile is the longest” when it comes to eradicating diseases with vaccines (NEJM 2013; 368: 1374-75).  The point the authors make is that as vaccines become successful, there is increasing refusal in communities to receive vaccines.  Few individuals may have direct or indirect experience with vaccine-preventable diseases when initial efforts are successful.

Much like bacterial resistance to antibiotics, individuals may become resistant to the use of vaccines when the perception of their utility dissipates.  As such, the authors note that eradication efforts going forward must not be a half-hearted effort. “If a disease such as measles is considered a priority by the global public health community, human and financial resources should be committed up front to a full-scale eradication initiative.”

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Linking diet, genes, and gut microbes to…heart disease

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A recent editorial (NEJM 2013; 368: 1647-49) helps explain the link between diet, genes, and gut microbes.  This editorial places in context a study, NEJM 2013; 368: 1575-84).  “The investigators found than dietary choline is metabolized by gut microbes to trimethylamine (TMA), which in turn is absorbed into the host bloodstream and metabolized in the liver to trimethylamine-N-oxide (TMAO).”  TMAO is thought to promote atherogenesis.

The study involved two phases.  In the first, using mass spectrometry, before and after suppression of gut microbes with antibiotics, they showed that a phosphatidylcholine challenge increased all choline metabolites; however, antibiotic use suppressed the formation of TMAO.

In the second phase, they looked at fasting plasma TMAO in relation to cardiovascular events in more than 4000 participants who underwent elective coronary angiography.  They identified an “independent, dose-dependent relationship between TMAO and the risk of a cardiovascular event.”

TMAO levels depend on the interaction between gut microbial production of TMAO which is affected by diet and by host genetic factors. The genetic factors are related to flavin-containing monooxygenases (FMO1 and FMO3); these enzymes oxidize TMA to TMAO are vary significantly in mice (and probably humans). With regard to diet, by limiting choline-rich foods (see links below regarding choline-rich foods) or by using probiotics, this may limit TMAO production and lower the risk of heart disease.

While these observations are intriguing, the mechanisms of TMAO in causing atherosclerosis and its primary function are unknown and much more information is needed to truly make these findings useful.  It is possible that TMAO is simply a biomarker of other factors.

One aside, the editorial states that our gut microbes contain “at least 100 times as many genes as our own genome.”

Take-home message: TMAO is a new potentially modifiable risk factor for atherosclerotic disease.

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