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.

IBS Symptoms in Patients with Celiac Disease

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While a gluten-free diet (GFD) is the optimal treatment, adult patients with celiac disease still have a high prevalence of irritable bowel symptoms (IBS) (Clin Gastroenterol Hepatol 2013; 11: 359-65).

The authors examined the prevalence of IBS symptoms by reviewing cross-sectional and case-control studies in adults with celiac disease (≥16 years old).  Initially, the literature search identified 624 studies; the vast majority did not fit the study requirements.  Seven studies (n=3383 participants) reported the prevalence of IBS symptoms in celiac disease.  These studies took place between 2002 to 2011 in five different countries.  IBS was defined using either Rome I, II, or III criteria.  Only one of these studies assessed adherence to a GFD by using negative tissue transglutaminase antibodies on the 2 most recent outpatient visits.

Results: IBS symptoms were present in 38% of all patients with celiac disease.  The pooled odds ratio was higher for celiac disease than controls (OR 5.6, with 95% CI 3.23-9.7).  Nonadherence to a GFD increased the likelihood over those who were adherent by an odds ratio of 2.69

Take-home message: IBS symptoms are present in a high proportion of patients with celiac disease.  While a GFD may improve these symptoms, some individuals will have persistent symptoms.

Related blog entry:

Is functional pain more common in children with … – gutsandgrowth  Previous blog entry examines functional abdominal pain in children and celiac disease.

Additional references:

  • -JPGN 2011; 53: 216. Case report of refractory celiac treated with 6-MP.
  • -Clincal Gastroenterol & Hep 2011; 9: 13. Celaic with persistent symptoms: consider poor adherence**, SBBO*, pancreatic insufficiency*/subclinical pancreatitis, refractory celiac (rare), PLE, giardia, malignancy, lactose intolerance, functional d/o*, microscopic colitis, Crohn’s*, NSAIDs
  • -Gastroenterol 2009; 136: 81, 91, 99, 32. Refractory celiac can be divided into 2 types; 2nd type assoc c abnormal IEL and has poor prognosis. Risk of non-hodgkins lymphoma 3.8-5 .3 fold over gen population in larg Sweish study. n=37869 c NHL, 236,408 controls, 613,961 1st degree relatives. Relatives c 2 fold risk. Absolute NHL risk ~1 in 1421 person-yrs for celiac pt.
  • -Clin Gastroenterol & Hep 2007; 5: 445-450. Causes of nonresponsive celiac.
  • -NEJM 2007; 356: 2548. Nonresponsive due to inhaled gluten in farm setting.
  • -Clin Gastro & Hep 2007; 5: 445. Gluten exposure in 36%, IBS n 22%, lactose intol 8%, refractory CD 10%
  • -Gastroenterol 2011; 141: 1187.  Prevalence of celiac similar in IBS as general population though higher number (7%) with celiac antibodies (esp gliadin).

Impaired Esophageal Function in Neurologically-Impaired Neonates

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There are a multitude of gastrointestinal problems that develop in infants who have hypoxic-ischemic encephalopathy (HIE).  One of the most pressing needs is determining how best to feed these infants.  A recent study provides more information on the aberrant esophageal function of these infants (J Pediatr 2013; 162: 976-82).

Design:  provocative esophageal manometry was performed in 34 neonates (27 with HIE and 7 controls).  HIE inclusion criteria included the following:

  1. >36 weeks gestational age
  2. acute perinatal event: abruption, cord prolapse, severe fetal heart rate abnormality
  3. signs of encephalopathy per Sarnat staging at birth

The characteristics of the HIE neonates is further defined and divided into those who were treated with hypothermia and those who received traditional care.  All but one infant had an abnormal brain MRI.

Key results:

  • Peristaltic reflexes, upper esophageal sphincter contractile responses (much greater in HIE patients), lower esophageal sphincter relaxation responses (much lower in HIE patients) and esophageal body coordination and clearance were all noted to be abnormal.
  • Infants treated with hypothermia had greater upper esophageal sphincter contractile responses and improved esophageal clearance (noted by decreased peristaltic durations).

Overall, this study demonstrates prolonged and poorly coordinated peristaltic responses in neonates with HIE.  There are no effective treatments for this type of esophageal dysmotility.  As such, even with current management approaches including gastroesophageal reflux medications and fundoplication, children with HIE remain at risk for aerodigestive malfunction and aspiration.

Related blog links:

Microparticles and Pediatric IBD

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Before reading a recent publication (JPGN 2013; 56: 401-07), I was not aware of microparticles; microparticles may play an important role in the development of venous thromboembolism (VTE).  Pediatric patients with inflammatory bowel disease (IBD) have a higher relative risk of VTE compared to their peers than individuals >60 years of age, though the absolute risk is low.  Much of the pathophysiology underlying the increased VTE risk remain uncertain.

Microparticles have been called “platelet dust” and are microvesicles that are released from the plasma membrane of many cells (leukocytes, red blood cells, endothelial cells, and platelets).

This study examined plasma samples from 33 pediatric patients with Crohn disease (CD), 20 pediatric patients with ulcerative colitis (UC), and 60 healthy controls. Subsequently, microparticles’ procoagulant activity was measured.  The CD and UC patients were consecutively enrolled from the outpatient clinic.  Only 3 patients in each IBD group was receiving a biologic therapy (infliximab). The disease activity and extent were compared with measures of procoagulant activity.

Several assays were undertaken to assess microparticles and thrombin generation. Key findings:

  • Increased procoagulant function of microparticles was identified in all CD patients (active and quiescent) and in UC patients with active disease.
  • A positive correlation was found between disease activity scores and procoagulant activity.

The authors note that elevated microparticles “may play a role in inflammation.” Inflammation and coagulation likely influence each other.  The authors note that VTE risk is greatest during flares but is still increased in patients in remission compared with controls.

The authors do not discuss the relationship of mucosal healing to microparticles or VTE. However, given that clinical remission is not defined currently based on mucosal healing, it would be of interest to know the status of these microparticles and the risk of VTE with mucosal healing. Perhaps the “quiescent” CD patients have ongoing disease contributing to their increased risk of VTE and increased procoagulation function of microparticles.

Related blog entry:

VTE with IBD | gutsandgrowth

**According to previous expert consensus guidelines, “routine heparin prophylaxis cannot be justified in children until better evidence is available to suggest that the benefit outweigh the risks”  (Turner D, et al. Am J Gastroenterol 2011; 106: 574-88).

For the pediatric pancreatologists

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Pancreatitis is a terrible affliction whether acute, recurrent or chronic.  While pediatric patients often have “mild” problems from acute pancreatitis, even in these cases the pain is usually severe and the treatment, which consists mainly of holding feedings and providing pain relief, does not impress anyone.

A few recent references do provide more data on several aspects of pancreatitis.

The first reference, J Pediatr 2013; 162: 788-92, provides data on the rare problem of acute necrotizing pancreatitis in children.  This retrospective study encompassing 21 years identified seven children.  CT scan showed necrosis of more than 30% and/or more than a 3 cm area in all of these patients.  Etiologies included medications (L-asparaginase, Valproate, Minocycline), diabetes (n=1), and gallstones (n=1).  No patients needed surgery or died.  After discharge, 5 patients had complications which included pseudocysts, diabetes, and pancreatic exocrine insufficiency.

Key points:

  • CT scan (with contrast) is useful in diagnosis and assessment of severity.
  • Initial presentation is similar to cases of acute pancreatitis without necrosis.  Long-term complications are increased.

The second reference: Gastroenterol 2013; 144; issue 6.  The entire issue is devoted to pancreas issues.  Pages 1272-81 review acute pancreatitis, pages 1282-91 review chronic pancreatitis, and pages 1292-1302 review genetic risk factors.

Page 1288 provides a suggested management algorithm for chronic pancreatitis:

Medical therapy recommendations include alcohol/smoking cessation, counsel regarding nutrition/vitamin D/calcium, consider analgesics (start with tramadol), consider adjuncts for pain (e.g.. neuron tin, SSRI, SSNRI, TCAs), assess exocrine and endocrine function (elastase and HgbA1C), use steroids if autoimmune pancreatitis.

If medical therapy ineffective, assessment of pancreatic duct is recommended.  Based on this information, discussion of endoscopic and surgical treatment is outlined as well.

Related blog entries:

Foil PNALD with FOLE?

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As noted on previous blog entries (see below), there has been significant enthusiasm for fish oil based lipid emulsion (FOLE) despite a lack of data showing superiority compared with standard soy-based lipid emulsions at similar dosing.  More data for FOLE helping infants with cholestasis are available (J Pediatr 2013; 162: 793-8).

Design: Single center, prospective observational study of 57 infants with parenteral nutrition-associated liver disease (PNALD) which  took place between 2007-2011.  All infants were between 2 weeks and 6 months of age at enrollment.  At enrollment, FOLE (Omegaven) at a dose of 1 g/kg/d was infused over 24 hrs.  FOLE which is not FDA-approved is available on a compassionate use protocol.

Infant characteristics: Median gestational age: 28 weeks. 47 of 57 were long-term survivors.  The median time at initiation of FOLE was 39.3 weeks post-menstrual age.

Results:

  • Median conjugated bilirubin at initiation of FOLE therapy was 7.5 mg/dL.
  • Resolution of cholestasis occurred at a median of 35 days (range 7-129) after starting FOLE.  Longer times for resolution were noted in those with higher initial bilirubin.
  • Time to resolution was inversely proportional to gestational age at birth (p=0.02) and directly to time to receive 100% calories enterally (p=0.03)

The authors note that none of the infants who died had liver failure; most deaths were due to multi-organ failure and sepsis.

In the discussion, the authors state “the most significant finding from this study is the effectiveness of FOLE in resolving cholestasis irrespective of the initial serum bilirubin values.”  I take issue with this statement primarily because the design of the study does not allow such attribution.  Without a randomized trial comparing FOLE to standard intralipids, this statement overstates any conclusion that can be drawn from this study.  Given the fact that resolution was correlated with advancement of enteral feedings, it is plausible that a similar result would occur with standard intralipids.

The authors make a number of other speculations about the potential superiority of FOLE over standard soy-based lipid emulsions, but concede that “our study was not adequately equipped to address” the association of reduced intralipid with improvement in cholestasis.  Despite this concession, the authors boldly proclaim in the concluding paragraph: “while awaiting the more general availability of FOLE, infants at high risk should be identified early and referred to centers that provide the option of FOLE…in which families are fully informed of both the potential benefits and limited current data.”

A recent media report also promotes the effectiveness of FOLE: http://nbcnews.to/11vbL2E 

Related blog posts:

“Tummy Time” Not Needed

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A recent NY Times article reviews a study which showed no benefit in motor development in babies who had “tummy time.”

Here’s the link: nyti.ms/11vrG11 

Here’s an excerpt:

Putting infants to sleep on their backs, recommended since the early 1990s, has helped reduce the prevalence of sudden infant death syndrome. ..Now a new study, published in May in the journal Early Human Development, suggests that tummy time may be irrelevant.

Canadian researchers compared 1,114 infants born from 1990 to 1992, just before the “back to sleep” campaign began, with 351 infants born 20 years later. They found no difference between the two groups in the age at which prone to supine or supine to prone rolling began, or in the order in which those behaviors appeared….

Whether tummy time helps or not, said the lead author, Johanna Darrah, a pediatric physical therapist at the University of Alberta, “the back to sleep campaign has not adversely affected motor development. Motor development happens.”

Codeine Contraindicated after Adenotonsillectomy

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Due to concerns outlined previously (Why “therapeutic dose” of codeine can kill | gutsandgrowth), the FDA has now placed a boxed warning on all codeine-containing products and is now contraindicated after adenotonsillectomy.  This is reviewed in a recent perspective article: NEJM 2013; 368: 2155-57.

“In the case of codeine, a combination of case reporting and our evolving understanding of genetic influences on drug response has clarified the need to avoid this drug after adenotonsillectomy.”

Bottomline: Due to the variability in codeine metabolism, alternative narcotic agents are usually a better choice even in those who have not undergone adenotonsillectomy.

High Rates of Helicobacter Pylori Resistance

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While the development of antibacterial resistance has broad implications, in gastroenterology patients specific problems have emerged with Helicobacter pylori (H pylori) and this has led to changes in first-line therapy( ).  More data on the treatment resistant H pylori has been published (JPGN 2013; 56: 645-48).

77 consecutive strains of H pylori  from Brazilian children and adolescents were isolated from gastric biopsies and analyzed; this study took place between 2008-2009 and the mean age was 11.1 years.  In 71 strains, there were no previous attempts at eradication.

Results:

  • 40% of strains were resistant to metronidazole
  • 19.5% of strains were resistant to clarithromycin
  • 10.4% of strains were resistant to amoxicillin
  • All strains were susceptible to furazolidone and tetracycline
  • 14/77 (18.2%) patients had multiple resistances

Take-home point: Resistance to antibiotics is altering our approach to H pylori therapy.  Antibiotic susceptibility testing may be needed to improve antibiotic selection and eradication rates.

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Switching from Thiopurines to Methotrexate

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Data regarding methotrexate treatment for Crohn’s disease (CD) is limited.  A fairly large retrospective study provides a better idea about its effectiveness over a five-year period (Clin Gastroenterol Hepatol 2013; 11: 667-72).

In total 174 consecutive CD patients (age 35 ±12 y) from 3 hospitals were analyzed.  All of these patients received methotrexate (MTX) after thiopurine therapy. 23% had not responded to an anti-TNF agent.  Most of the patients who had failed thiopurine treatment had an intolerance to thiopurine rather than loss of clinical response.  Data on patient characteristics including smoking status, disease behavior/location, previous treatments, and indication for MTX are detailed in Table 2.  Interestingly, 113 patients were female.  The authors noted that 90% of their patients received MTX parenterally.

Key findings:

  • Patients with sustained clinical benefits from methotrexate monotherapy:  98 (86%) at 6 months, 50 (63%) at 12 months, 27 (47%) at 24 months, and 3 (20%) at 60 months.
  • 45 (26%) discontinue methotrexate due to intolerance, mostly within the first 6 months.  However, adverse effects were generally mild.  Only one patient required hospital admission for an infection (cytomegalovirus).

There are many limitations of this retrospective study.  Nevertheless, a significant portion of patients derived clinical benefit for at least 2 years.

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Neurological Complications Associated with Inflammatory Bowel Disease

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Though I have not seen much in the way of neurological complications in our pediatric inflammatory bowel disease (IBD) population, nevertheless I worry about them.  A recent article provides some insight into the incidence, the pathophysiology and approach to these complications (Inflamm Bowel Dis 2013; 19: 864-72).

Types of neurologic complications: The most common neurologic complication is peripheral neuropathy.  The frequency is quite variable based on data collection method.  In large administrative healthcare data, the prevalence has been reported around 2% whereas in cohort studies the range has been 8-15%. Other complications include meylopathy, cerbrovascular disease, cranial nerve palsy (eg. Melkersson-Rosenthal syndrome), seizures, and demyelinating diseases.

With regard to demyelinating diseases, this has gained additional attention in the setting of biologic agents which have been associated with this complication.  However, the authors note that a pre-biologic treatment study from Olmstead County, observed a prevalence of multiple sclerosis of 1% which was 3.7 times higher than expected.  In addition, similar studies have confirmed this finding.

Potential mechanisms vary greatly depending on the neurologic complication. With regard to cerebrovascular disorders, “venous thromboembolism (VTE) has been shown to occur 3 times more frequently in patients with IBD (the risk increases to 8-10-fold in patients with active colitis) than the general population.”  Hence, VTE prophylaxis is recommended by the authors in hospitalized IBD patients, especially if they are experiencing a disease exacerbation.

In addition to the underlying disease, vitamin deficiencies (eg. Vitamin B12) and medications can trigger neurologic complications.

  • Natalizumab: progress multifocal leukoencephalopathy (PML)
  • Metronidazole: peripheral neuropathy (typically reversible with drug discontinuation)
  • Anti-TNF-α agents (infliximab, adalimumab, certolizumab): demyelination, rarely seizures, and rarely PML
  • Cyclosporine: various neurotoxicity in ~25%

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