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.

Liver Shorts -February 2021 (part 1)

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T Mayr et al. JPGN 2021; 72: 115-122. Optimized Trientine-dihydrochloride Therapy in Pediatric Patients With Wilson Disease: Is Weight-based Dosing Justified?

In this retrospective study with 31 children with Wilson’s disease (most of whom had had previous penicillamine), those who received more than 20 mg/kg/day of trientine therapy had increased adverse effects compared to those who received less than 20 mg/kg/day: 63% vs 7%; median followup was 60 months. In addition, there was not increased response to higher doses. The authors note that trientine had lower incidence of adverse effects compared to penicillamine and “appears to be the preferred” as a first-line treatment.

J Teckman et al. (ChiLDReN Network). J Pediatr 2020; 227: 81-86. Longitudinal Outcomes in Young Patients with Alpha-1-Antitrypsin Deficiency with Native Liver Reveal that Neonatal Cholestasis is a Poor Predictor of Future Portal Hypertension

In this prospective cohort with 350 participants (all with either PiZZ (90%) or PiSZ (10%) and native livers), 278 (79%) entered the cohort (in 2007 or later) without portal hypertension and 18 developed portal hypertension during follow-up. Portal hypertension was defined by development of ascites, varices or combination of splenomegaly/thrombocytopenia. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. Median length of followup was 2.5 years. My take: While most children with Alpha-1-Antitrypsin Deficiency do well, monitoring is warranted as some will develop progressive liver disease (even in the absence of neonatal cholestasis).

SA Harrison et al. Gastroenterol 2021: 160: 219-231. Full text PDF: Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis

In this phase 2 double-blind study with 78 patients with NASH, at week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%) (P=.002). Fibrosis improvement (1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of
patients receiving placebo (P = .10). And, NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20)

A Chanpong, A Dhawan. JPGN; 2021: 72: 210-215. Long-Term Urinary Copper Excretion on Chelation Therapy in Children with Wilson Disease Key finding:  24-hour UCE decreases to ≤8 μmol/day and <6 μmol/day after 1 and 5 years of treatment, respectively.

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Why Observational Studies Are Misleading & PPI Association with Kidney Stones

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M Simonov et al. Clin Gastroenterol Hepatol 2021; 19: 72-79. Use of Proton Pump Inhibitors Increases Risk of Incident Kidney Stones

Commentary: P Moayyedi. Clin Gastroenterol Hepatol 2021; 19: 41-42. Full Text Link: Leaving No Stone Unturned in the Search for Adverse Events Associated With Use of Proton Pump Inhibitors

 The retrospective study by Simonov et al used data from the Women’s Veteran’s Cohort Study (1999-2017) with 465,891 patients. Key findings:

  • Overall, 2.4% of the cohort developed kidney stones. PPI use was associated with kidney stones in the unadjusted analysis, hazard ratio [HR], 1.74 (95% CI, 1.67–1.82), and persisted in the adjusted analysis with HR, 1.46 (CI, 1.38–1.55). The association was maintained in a propensity score-matched subset of PPI users and nonusers (adjusted HR, 1.25; CI 1.19–1.33).
  • H2RAs were also associated with increased risk with adjusted HR, 1.47

While this study is interesting, the editorial provides a great deal of insight into how this study and many others can be misleading. Key points:

  • “It seems that every few months a new issue arises, with the list of problems that PPIs might cause becoming ever longer, including pneumonia, fracture, heart disease, Clostridium difficile–associated diarrhea, dementia, chronic kidney disease, low B12 levels, gastric cancer, and even all-cause mortality.”
  • If the findings in the study are correct, with the unadjusted HR, “this translates to a number needed to harm (NNH) of 365 patients who need to take PPIs for 1 year to observe 1 extra episode of kidney stones…if the adjusted HR is used …the NNH was 1550.”

Limitations:

  • Confounding variables are hard to eliminate in an observational study. “Studies usually show that patients who are prescribed PPIs are, on average, sicker than those who are not taking these drugs.”
  • In the only large randomized controlled study (>17,000 patients over 3 years) of PPIs, there was no difference in pneumonia, Clostridium difficile infection, fracture, gastric atrophy, chronic kidney disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality in the PPI compared with the placebo arms.”Enteric infections, which were slightly more common in patients randomized to PPIs, but even there the NNH was more than 900 per year.”
  • Biases undermine the interpretation of observational studies. One example for PPIs is its association with pneumonias in prior observational studies.
    • “The effect was strongest within the first week of prescription when the odds ratio was approximately 4, although this was reduced to approximately 1.5 after 1 month. This marked reduction in risk over a relatively short period of time is not biologically plausible and a more likely explanation is that the association is the result of protopathic bias. Patients presenting to the clinician with a cough may be diagnosed with silent reflux and given a PPI. A few days later other symptoms develop, and pneumonia is made as the final diagnosis. This will not be apparent when simply interrogating a database where the researcher will observe that a PPI was prescribed before the onset of pneumonia and will imply the association is causal when this is not the case.”
  • This same type of bias could be present with the association between PPI and kidney stones.
    •  “Patients may present with abdominal pain and be given a PPI as a therapeutic trial, assuming the pain may be acid-related when subsequently it is found that the pain relates to kidney stones. Simonov et al reported that 3% were prescribed PPIs within 1 month of the diagnosis of kidney stones, but did not provide the analysis that would allow us to interpret whether protopathic bias may play a role in the associations observed”

My take: It is unlikely that PPIs cause kidney stones; however, if this is a risk factor, it is very rare. Understanding how PPIs have been incorrectly linked to a multitude of problems is a valuable lesson for any practitioner and emphasizes the need for randomized controlled studies to determine medication safety.

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Can Necrotizing Enterocolitis Be Prevented with Antibiotics?

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Y Li et al. J Pediatr 2020; 227: 128-134. Early Use of Antibiotics Is Associated with a Lower Incidence of Necrotizing Enterocolitis in Preterm, Very Low Birth Weight Infants: The NEOMUNE-NeoNutriNet Cohort Study

Methods:  This study used the NEOMUNE-NeoNutriNet cohort of VLBW infants from 13 neonatal intensive care units (NICUs) in 5 continents (n = 2831). NEC incidence was compared between infants who received early antibiotics and those who did not.

Key finding:

  • The incidence of NEC was 9.0% in the group of infants who did not receive early antibiotics (first 72 hrs) (n = 269), compared with 3.9% in those who did receive early antibiotics (n = 2562)

This type of study is inherently difficult due to measured and unmeasured confounders. In a related commentary, Joseph Cantey (Early Antibiotic Therapy and Adverse Outcomes in Preterm Infants: Time for a Trial!, https://doi.org/10.1016/j.jpeds.2020.07.046) notes that some previous studies have shown an association of antibiotics with increased risk of NEC, presumably due to a selection bias (eg. sicker patients getting antibiotics). Fortunately a randomized prospective trial is underway, the NICU Antibiotics and Outcomes (NANO, NCT03997266). This should help determine more carefully the risks and benefits of antibiotics in this vulnerable population.

My take: We have a lot to learn about modulating the premature infant’s microbiome to prevent necrotizing enterocolitis.

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Case report: NEJM 2020; 383: 25: 2461. Patient who weighed 520 gram at birth (23 week gestation) developed NEC; she recovered and all orally fed at time of discharge.

Is It Safe to Exclude Central-Line Infections at 24 hrs?

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A recent study (GL Fell et al. J Pediatr 2020; 227: 69-76. Optimizing Duration of Empiric Management of Suspected Central Line-Associated Bloodstream Infections in Pediatric Patients with Intestinal Failure) showed that 98% of blood cultures returned positive within 24 hrs.

This prospective single-institution cohort study with 73 patients had 128 Central Line-Associated Bloodstream Infections (CLBSI) in 35 patients during the study period (2015-2018).

Key findings:

  • The probability of a blood culture becoming positive after 24 hours was 2.3%; only 1 blood culture became positive after 30 hours (none beyond 48 hrs).
  • The median time from blood sampling to positive culture was 11.1 hours.
  • Elevated C-reactive protein and neutrophil predominance in white blood cell count were associated with positive blood cultures

My take: 98% is not good enough. For now, 48-hours is the safest policy.

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Bahai Temple in Wilmette, IL

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Lots of Room to Improve with H pylori Treatment

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Briefly noted: A recent survey study (N Du et al. JPGN Reports: 2021; 2: p e033. doi: 10.1097/PG9.0000000000000033. Full Text: Assessment of Community Pediatric Providers’ Approach to Children With Helicobacter pylori) found that pediatric providers had poor knowledge and/or adherence to pediatric H pylori guidelines.

Key findings:

  • Over a third of the respondents reported incorrectly testing patients for H. pylori while they were taking proton pump inhibitors.
  • 17% (n=17) incorrectly preferred blood serology as testing modality
  • 63% (n=64) relied on symptom resolution as indication of cure

My take: It would be interesting to compare pediatric gastroenterology provider responses to general pediatric providers. It is likely that a much higher percentage would be following established guidelines. One area of the guidelines that I think should be changed would be encouraging increased use of quadruple therapy in children, especially if resistance testing is not performed; this change would better align with adult guidelines. In adults, quadruple therapy has been associated with increased cure rates.

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Data on Immobilized Lipase Cartridge for Patients with Cystic Fibrosis

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Full text: M Sathe et al. JPGN 2021; 72: 18-23. Evaluation of the Effectiveness of In-line Immobilized Lipase Cartridge in Enterally Fed Patients With Cystic Fibrosis

Background: Traditional pancreatic enzyme replacement therapy is not designed for use with enteral feedings. “Only 1 FDA-approved PERT (PERTZYE, Cheisi, Inc.) has a package insert with instructions on how to deliver the contents of the lowest dose capsule (4000 USP lipase unit) through gastrostomy tubes 14 French or larger…Two recently published studies demonstrated the safety, tolerability, and effect on FA absorption of a new enzyme strategy to aid fat digestion with continuous enteral feedings, a single use digestive cartridge containing immobilized lipase (RELiZORB; Alcresta Therapeutics, Newton, MA). The cartridge connects in-line with an enteral feeding set. As enteral formula flows through the cartridge, immobilized lipase enzyme hydrolyzes intact triglyceride fats within the formula into more absorbable forms, whereas the lipase is retained within the cartridge.”

Key findngs:

  • Weight percentiles reached 50% in 18%, 25.5%, and 28.9% of patients at 0, 6, and 12, respectively.
  • BMI reached 50% in 37.1%, 49.1%, and 50.0% in patients at 0, 6, and 12 months, respectively.

My take: “Immobilized lipase cartridge use demonstrated statistically significant improvements in growth in patients with cystic fibrosis requiring enteral feedings.” Newer and more effective therapies for Cystic Fibrosis may decrease the need for enteral supplementation along with lipase cartridge.

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Does It Make Sense to Look for Celiac Disease in Children with Functional Constipation?

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A recent study (AC Fifi et al. J Pediatr 2020; 227: 77-80.Full text PDF: Celiac Disease in Children with Functional Constipation: A School-Based Multicity Study) shows that celiac disease was not more prevalent in Colombian children with functional constipation(n=203) than in matched healthy controls (n=419). Patients were recruited from public schools.

Key finding:

  • The overall prevalence of celiac disease in the entire cohort was 0.6%. Of those with functional constipation, 1 (0.5%) was diagnosed with celiac disease, and 3 (0.7%) of the control patients

The authors note that some prior publications (references 11 and 12) have found a slight increase risk of celiac disease in children with constipation.

My take: In children with functional constipation, the yield from testing for celiac disease is very low and probably not significantly greater than the general population. In children with irritable bowel syndrome (which is often confused with constipation), the yield is probably a bit higher.

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A New FDA Warning for Tofacitinib

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2/4/21: FDA: Initial safety trial results find increased risk of serious heart-related problems and cancer with arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib)

“The U.S. Food and Drug Administration (FDA) is alerting the public that preliminary results from a safety clinical trial show an increased risk of serious heart-related problems and cancer with the arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib) compared to another type of medicine called tumor necrosis factor (TNF) inhibitors. FDA required the safety trial, which also investigated other potential risks including blood clots in the lungs and death. Those final results are not yet available….

Patients should not stop taking tofacitinib without first consulting with your health care professionals, as doing so may worsen your condition. Talk to your health care professionals if you have any questions or concerns.”

Related blog post: FDA Warning on Tofacitinib (July 2019)

Growth in Inflammatory Bowel Disease: Better Late Than Never

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Briefly noted: N Gupta et al. Inflamm Bowel Dis 2020; 26: 1880-1889. Continued Statural Growth in Older Adolescents and Young Adults With Crohn’s Disease and Ulcerative Colitis Beyond the Time of Expected Growth Plate Closure

In this retrospective observational longitudinal cohort study with 3007 patients with IBD from the ImproveCareNow Network, the authors found a high rate of continued linear growth after expected growth plate closure (15 years in females, 17 years in males).

Key findings:

  • 80% manifested continued growth beyond the time of expected growth plate closure, more commonly in CD (81%) than UC (75%; P = 0.0002)
  • Median height gain was greater in males with CD (1.6 cm) than in males with UC (1.3 cm; P = 0.0004), and in females with CD (1.8 cm) than in females with UC (1.5 cm; P = 0.025)

My take: This study provides additional information about delayed skeletal maturation in the pediatric population with inflammatory bowel disease. Interestingly, the rate of continued growth with ulcerative colitis was nearly as high as with Crohn’s disease.

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Statin Use May Help in Fatty Liver Disease

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J Lee et al. The American Journal of Gastroenterology: January 2021 – Volume 116 – Issue 1 – p 116-124. Full text link: Effects of Statin Use on the Development and Progression of Nonalcoholic Fatty Liver Disease: A Nationwide Nested Case-Control Study,

Using more than 11 million subjects enrolled in Nationwide Korean database, the authors explored the associations between statin use and fatty liver disease in adults (20 yrs or older).

Key findings:

  • The use of statin was associated with a reduced risk of NAFLD development (adjusted odds ratio [AOR] 0.66; 95% confidence interval [CI] 0.65–0.67). NAFLD was diagnosed by calculating fatty liver index (FLI).
  • The use of statins reduced the risk of significant liver fibrosis (AOR 0.43; 95% CI 0.42–0.44). Fibrosis was based on a BARD score ≥ 2.

The effects of statins may be mediated by anti-inflammatory and antifibrotic actions, which have been evident in experimental models of chronic liver disease.

My take: Statin use appears beneficial in patients with NAFLD. Since dyslipidemia is frequent in patients with NAFLD, there should be a low threshold for using statin therapy.

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