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.

Understanding chromosomal microarrays

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The advantages and disadvantages of chromosomal microarrays are highlighted in a recent article and a related editorial (NEJM 2012; 367: 2175-84, 2249-51).

Chromosomal microarrays can detect almost all of the chromosomal imbalances detected with conventional cytogenetic analysis.  They are recommended as a first-tier test for postnatal developmental delays, autism spectrum, or with multiple congenital anomalies.  Clinically significant findings occur in 15% of those with normal conventional karyotypes.

Specific advantages of microarrays:

  • Higher resolution
  • Faster turnaround due to automation
  • Does not require dividing cells (useful in fetal death)
  • Eliminates need to culture amniocytes or chorionic villi

Major downside:

  • In a few percent, may detect copy-number variant of uncertain clinical significance
  • Increased cost

The referenced study compared chromosomal microarray to karyotyping and enrolled 4406 women at 29 centers who were undergoing prenatal diagnosis.  Indications for screening included advanced maternal age (47%), abnormal result on Down’s syndrome screening (19%), structural abnormalities on ultrasonography (25%), and other indications (9%) (some had multiple indications).

The microarrays were of two varieties.  The first microarray (71% of cases) consisted of a fourplex array with each array consisting of 44,000 oligonucleotide probes.  The second platform (29% of cases) contained 1.8 million  oligonucleotide probes.

Key Findings:

  • Microarray identified all of the abnormalities on conventional karyotyping except for balanced translocations (no loss of genetic material).
  • There were 94 of 3822 fetal samples with copy-number variants of uncertain clinical significance (see blog reference below).  Subsequently, 30 of these were classified as pathogenic and 8 as benign.
  • In samples with normal karyotypes, microarray identified clinically relevant findings in 6% of those with a structural abnormality and 1.7% of those with advanced maternal age or positive Down’s syndrome screening.

The implications of this study and related studies are that microarray has a role in prenatal evaluation of structural abnormalities.  Ultimately, whole-exome sequencing will likely supersede microarray analysis and further the conundrum of interpreting abnormalities of uncertain clinical significance.

Related blog entry:

Failure of PPI test

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Identifying patients gastroesophageal reflux with a so-called ‘PPI test’ is not effective (Clin Gastroenterol Hepatol 2012; 10: 1360-66).

This study examined data from the previous Diamond study (Gut 2010; 59: 714-21).

In short, among 308 patients who were evaluated by endoscopy and pH probe, 197 had GERD identified by the presence of reflux esophagitis, pH <4 for 5.5% or positive symptom association monitoring.  Then all patients were given esomeprazole 40 mg once a day for two weeks.

A positive response to PPI Rx was observed in 69% of those with GERD and in 51% of those without GERD.  If response was defined as ‘the absence of the most bothersome symptom in the last 3 days of treatment,’ then GERD patients had a 54% response compared to 35% of Non-GERD patients.

While the PPI test is a failure, in many clinical situations, symptom response to therapy may be more important than the reason for the symptoms. The attached link provides a nice synopsis: Study Finds ‘PPI Test’ a Poor Predictor of GERD : Internal Medicine …

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Ethanol locks -jump on the bandwagon

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http://ncp.sagepub.com/content/early/2012/12/10/0884533612468009.abstract

From Nutrition in Clinical Practice, published online before print, December 11, 2012, doi:10.1177/0884533612468009 (Thanks to Kipp Ellsworth for this link from his twitter feed):

“Our group of patients (n=14) showed a 73% reduction in CABSIs and a 77% reduction in catheter removal due to infection after ethanol lock therapy. In our patient population, weekly ethanol lock therapy for 2 hours is an effective technique to reduce CABSIs and catheter removal in long-term home PN patients.”

CABSIs =catheter-associated bloodstream infections

Another option for line locks

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A pediatric study from London with 19 patients demonstrates the utility of taurolidine line locks (JPGN 2012; 55: 403-7).

Taurolidine has broad antimicrobial activity against Gram-positive and Gram-negative bacteria in addition to antifungal properties.  Also, taurolidine prevents biofilm formation which can help minimize colonization of catheters.  It acts by binding to the cell walls of organisms; this results in the prevention of bacterial adhesion to biological surfaces. TauroLock™ | TauroLock™

15 of the 19 patients had a history of recurrent central catheter infections and 4 were started on the line locks empirically.  At the completion of the parenteral nutrition, 0.7 to 1 mL of the taurolidine solution was instilled and left for at least 12 hours.

Taurolidine-treated patients had 1.1 episodes per 100 catheter days of CVL infections; this compared with a rate of 8.6 episodes per 1000 catheter days for heparin control.  Furthermore, 74% (14) had no infections for up to 33 months after changing to taurolidine.  No reports of mulitresistant organisms or adverse effects were reported.  Taurolidine is nontoxic for humans and rapidly metabolized to taurine, carbon dioxide, and water.

To my knowledge, taurolidine is not available in the U.S.  Nevertheless, the data on line locks indicate that antimicrobial line locks are associated with reductions in catheter infections.

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Additional reference:

Improvement in obesity rate?

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In case you didn’t see it, this article link, OBESITY IN YOUNG IS SEEN AS FALLING IN – THE NEW YORK TIMES, appeared in multiple news outlets (December 10, 2012) and suggests that in some cities there has been a modest reduction in obesity rates of 3-5%.

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Best strategy for dose escalation of infliximab

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At least 50% of patients with long-term infliximab therapy require dose escalation.  However, dose escalation can mean doubling the dose or shortening the infusion interval.  So which strategy is best?  A recent article provides some insight into this question (Inflamm Bowel Dis 2012; 18: 2026-33).

In this multicenter retrospective study of 168 Crohn’s disease (CD) patients, the outcome of patients who had dose-doubling (n=112) to 10 mg/kg/dose/8 weeks was compared with patients whose infusion intervals were halved to 5 mg/kg/dose/4 weeks (n=56).  The entire cohort had a mean age of 25 years and a mean disease duration of 12 years.  39% had a history of previous intestinal surgery.  Concurrent use of thiopurines was noted in 68% and concurrent use of methotrexate in 4%.

Sustained response at 1 year to dose-doubling strategy was 50% compared with 39% in the interval-halving group.  Favorable factors included nonsmoking status, normal C-reactive protein, and CD diagnosis between 16-40 years of age.

It is noted that a subsequent dose escalation was experienced by 28 of the 87 patients who had loss of response after first dose escalation.  Regained response occurred in 9 (32%) of this cohort.

The authors indicate that increasing the dose to 10 mg/kg/8 weeks is likely preferable due to convenience and cost.  At the same time, it is apparent that shortening the infusion interval is not likely to be more effective than dose doubling.

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Does bone density improve with IBD therapy?

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Long term followup is needed to determine the significance of low bone mineral density (BMD) in children and adolescence with IBD; data with 2 year followup is available (JPGN 2012; 55: 511-18).

In this study from Sweden, 144 patients with IBD were enrolled and 126 were available at 2-year followup (2003-2005).  Among the 144 patients, there were 93 males and 83 with UC. Low BMD was noted in children with both UC and CD for the lumbar spine at baseline and no improvement was noted at 2 years.  Only boys had lower BMD z scores for the lumbar spine (LS) (-1.1); girls had normal LS z scores (0).

While the investigators could not demonstrate catch up in bone mineral density, they note that gains in BMD may accrue beyond late adolescence into early adulthood; this takes place after completion of linear growth.  In the subgroup of subjects in early adulthood, there was improvement in BMD:

  • For boys: from -1.7 at baseline (age 17.9) to -0.5 at followup (age 20.0)
  • For girls: from -0.4 at baseline (age 17.1) to 0.4 at followup (age 19.2)

With greater use of biologic therapy, these data are likely to change.  Among medical treatments, only biologic therapies have been shown to improve bone formation and improve catchup growth.

Related blog entry:

Additional references:

  • -JPGN 2011;53: 361. Similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for low bone mineral density in IBD.
  • -JPGN 2009; 48: 538. Need to adjust bone density for bone age.
  • -Gastroenterol 2009; 136: 123. Longitudinal bone health study. Steroids did NOT adversely affect bones. n=78.
  • -Clin Gastro & Hep 2008; 6: 1378. IFX improves biomarkers of bone formation.
  • -J Pediatr 2008; 153: 454, 484. Use of biomarkers of bone turnover in Crohn dz; even when controlling for other factors like delayed bone age, delayed puberty, etc, still evidence of decrease bone formation and increased resorption.
  • -JPGN 2007; 45: 538. Ca/Vit D supplements -no change in BMD in IBD patients over 12 months.
  • -Clin Gastro & Hep 2007; 5: 721. DXA may not predict risk well.
  • -IBD 2007; 4: 416. Inflammation, not steroids, is key factor in bone mineral density.
  • -IBD 2006; 13: 42. Natural hx of bone mineral density in IBD; steroid dose did not correlate with BMD. Children did not have “catch up” bone density.
  • -JPGN 2006; 43: 597. Crohn’s patients had similar rate of fractures as siblings w/o IBD.
  • -Clin Gastro & Hep 2006; 4: 152. Osteoporosis in IBD.
  • -IBD 2006; 12: 797. Review of bone mineral density with IBD
  • -Clin Gastro & Hepatol 2005; 3: 113-121, 122-132 & editorial 110. In 1st article, budesonide better for bones than other steroids. In 2nd article, unable to show benefit of addition of etidronate to Ca++/Vit D.
  • -NEJM 2002; 351: 868. Intermittent steroids in nephrotic syndrome did NOT change bone mineral density.
  • -Gastro 2001; 121: 1485-88. Tanning bed Rx of vitamin D deficiency.
  • -Gastro 2000; 119: 639-46. Alendronate increases BMD in pts c Crohn’s
  • -NEJM 1998; 339: 292-9/ J Bone Miner Res 2000; 15: 1006-13. Bisphosphonates effective in steroid-induced bone disease

False-positive serology for Celiac disease

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It is prudent to exercise caution in establishing a diagnosis of Celiac disease (CD) in young asymptomatic children who are identified with screening serology (J Pediatr 2012; 161: 980-14).

In this Italian study, a nationwide, multicenter, prospective intervention trial was established to assess the role of age at gluten introduction on development of CD.  Subjects were recruited at birth who were at increased risk for CD; they had at least one first-degree relative with CD.

In their cohort, 96 children were identified.  In addition to having an affected first-degree relative, all children had positive serology (21 with positive tissue transglutaminase IgA antibody [tTG] and 1 with IgA deficiency/positive gliadin IgG antibody) and results of a small intestinal antibody.

While 72 had definitive CD, 24 were considered potential CD (serology positive/Marsh 0-1 histology) and asymptomatic.  The fascinating part of this study was the followup of the potential CD cases –21/24 continued on a regular diet.  Only 1 developed overt CD. 18 (86%) developed normal serology and 2/21 had fluctuating antibody levels after two years.

Based on their findings as well as consensus guidelines, the authors propose that asymptomatic young patients with abnormal serology should be followed for at least 3-6 months as long as tTG < 11 times ULN.

Other findings:

  1. Breastfeeding may have a protective role; individuals with overt CD had a shorter mean duration of breastfeeding than the potential CD group (4.2 months compared with 5.1 months).
  2. Gluten introduction at age 6 months did not increase risk of overt CD (compared to potential CD) relative to introduction at 12 months.

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How to dissolve a bezoar

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Some bezoars, like lactobezoars, can resolve quite easily often with intravenous fluids.  Trichobezoars often require surgery.  Phytobezoars can dissolve with  diet coke and cellulase (Gastroenterol Hepatol 2012; 8: 770-72).

A phytobezoar, which is the most common type, is composed of indigestible fruit and vegetable fibers and occur in the setting of impaired gastric motility.  In the three cases presented, the combination of diet coke and an over-the-counter cellulase (Enzymedica Digest Gold) which contains 3000 units of cellulase per capsule was successful at dissolution of the phytobezoars over a 6-8 week period.

The role of the diet coke is less certain.  The sodium bicarbonate in sodas and the penetration of carbon dioxide bubbles may have facilitated dissolution.  Additionally, the acidic pH (2.6) of Coca-Cola along with the phosphoric and carbonic acids may have been beneficial.  While Coca-Cola and Diet Coke have the same potential mechanism of action, Diet Coke is easier to administer in diabetic patients.

Additional references:

More on entecavir and tenofovir

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In a previous post (Extended data with entecavir & annotated HBV management …) good news on the long term use of entecavir was reported.  Another large study indicates that  entecavir (ETV) monotherapy generally produces equivalent results to combination therapy with tenofovir (TDF) (Gastroenterol 2012; 143: 619-28).

The authors report their experience with a randomized open-label multi center study with 379 nucleos(t)ide-naive patients; 264 were HBeAg-positive and 115 were HBeAg-negative.  At week 96, among all patients, virology response defined as HBV DNA <50 IU/mL was 76.4% in the ETV group and 83.2% in the ETV-TDF group.

In multiple comparisons, the combination group tended to have better virological response  except in the HBeAg-negative group (91.1% ETV vs. 89.8% in ETV-TDF).  The other comparisons included the HBeAg-positive group (69.8% ETV vs. 80.4% ETV-TDF), low baseline HBV DNA (<10 to the 8th IU/mL) (83% in both groups), and the high baseline HBV DNA (62.0% ETV vs. 78.8% ETV-TDF).  Yet, the only group where this was statistically significant was those with high baseline HBV DNA, n= 164 (>10 to the 8th IU/mL).

Biological response was greater in the ETV monotherapy, 81.9% compared with 69% in the combination group.  Among HBeAg+ patients, loss of e antigen was comparable: 38.9% in ETV compared with 29.7% in ETV-TDF.  In this group, seroconversion to HBeAb+ occurred in 32.5% of ETV compared with 21.7% of combination patients.

Safety: five patients in combination group and two patients in ETV monotherapy group discontinued treatment due to adverse events.  Three deaths occurred in the combination group (either on treatment or during followup), with the following causes: cardiac arrest, bile duct tumor, and liver failure.  In the patient with liver failure, she had responded to therapy but experienced a breakthrough at week 48.  At week 100, she was switched to commercial treatment.  Five days later she was hospitalized and died within 1 week.  No resistance to either drug was identified.  Thus, the authors speculate that nonadherence was an important factor.  Also, during the course of the study, five malignancies were diagnosed, including 3 with HCC.