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.

Gluten-Free Diet –Role in IBS?

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MI Pinto-Sanchez et al. Clin Gastroenterol Hepatol 2021; 19: 2343-2352. Open Access: Gluten-Free Diet Reduces Symptoms, Particularly Diarrhea, in Patients With Irritable Bowel Syndrome and Antigliadin IgG

In this prospective study of 50 patients with IBS (ROME III, all subtypes), with and without serologic reactivity to gluten (antigliadin IgG and IgA), and 25 healthy subjects (controls) were studied before and after 4 weeks of a GFD. Celiac disease (CD) was ruled out in patients and controls by negative tissue transglutaminase (tTG) IgA antibody and deamidated gliadin IgA or IgG antibodies and by the absence of mucosal atrophy in a duodenal biopsy specimen (Marsh 0 or 1). At least 4 and 2 biopsy specimens were obtained from the second and the first part of the duodenum, respectively.

Key findings:

  • Compared with baseline, IBS symptoms improved in 18 of 24 patients (75%) with antigliadin IgG and IgA and in 8 of 21 patients (38%) without the antibodies
(A) Improvement in IBS symptoms (>4.5 points in the total Birmingham score) in antigliadin antibody (AGA)+ and AGA– patients after GFD. (B) Change in IBS symptoms after a gluten-free diet (GFD) compared with baseline in AGA+ and AGA– patients.

The associated editorial (A Rej et al. Open Access: Personalizing Dietary Therapies For Irritable Bowel Syndrome: What Is Gluten’s Role?) provides some useful points:

  • “A key trigger for symptom generation in IBS is diet, with more than 80% reporting food-related symptoms…It seems that wheat is a key component for symptom generation in IBS, as demonstrated by a study in 920 patients by Carroccio et al,8 which identified wheat sensitivity in 30% of patients”
  • The authors note that the Pinto-Sanchez population had a higher-than-expected rate of AGA positivity of 50% when previous studies have found rates of 7-18%.

My take: This prospective study indicates that a GFD is associated with clinical improvement in a significant number of individuals with IBS (with and without antigliadin antibodies) who did not report any gluten sensitivity or were not on a gluten-restricted diet before study entry. Based on a number of other studies, however, it seems that a low FODMAPs diet is likely to have a higher efficacy for patients with IBS.

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Trisomy 18 Trends over the Last 20 Years

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TA Fick et al. J Pediatr 2021; 239: 206-211. Trisomy 18 Trends over the Last 20 Years

Methods: A retrospective analysis using the Kids’ Inpatient Database from 1997 to 2016 (10,151 admissions) was performed for trisomy 18.

Key Findings:

  • Gastrostomy tube placement increased 12-fold during the study period, tracheostomy increased 11-fold, and cardiac intervention increased 5-fold
  • The overall mortality rate (based on inpatient data) decreased in those with trisomy 18 from 32% in 1997 to 21% in 2016
  • Limitations: their data are limited to only hospitalized children and do not include all patients with trisomy 18 or capture population incidence

My take: This study documents a change in the approach to treating children with Trisomy 18. Compared to 20 years ago, these children are being offered more medical/surgical treatments rather than only palliative interventions.

Genetic Underpinnings of Acute Liver Failure in Children

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R Hegarty et al. J Pediatrics; 236: 124-130. Open Access: Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology

Background: “Despite the progress made over the last 40 years the rate of indeterminate cases [of acute liver failure] remains ~30%”

Methods: The authors identified 41 children (<10 yrs) with DNA sample availability who were admitted to King’s College Hospital, London, with ALF of indeterminate etiology (2000-2018). In addition, trio exome sequencing was performed on 4 children admitted during 2019.

Key Findings:

  • Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively
  • The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings.

My take: Genetic testing for underlying metabolic/metabolic disorders is important to further determine the reasons for ALF. Given the potential need for liver transplantation, obtaining these results quickly will be crucial. In addition, interpretation of the results in some cases will be difficult.

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Emerging Data on Risankizumab for Crohn’s Disease

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From Gastroenterology and Endoscopy News: New Anti–IL-23 Therapy Shows Benefit in Crohn’s Disease

An excerpt:

Two phase 3 placebo-controlled trials with the immune modulator risankizumab demonstrated control of Crohn’s disease whether or not patients had previously received a biologic agent.

Rates of clinical remission at 12 weeks with the interleukin (IL)-23 inhibitor risankizumab (Skyrizi, AbbVie), were about 48% in patients without prior exposure to biologic therapy and more than 40% in those with prior exposure…

The two trials, ADVANCE and MOTIVATE were presented together at the 2021 Digestive Disease Week (abstract 775a)…

Only 12% of patients in the placebo group achieved endoscopic remission versus 40.3% of those on the 600-mg dose of risankizumab (P<0.001). [Rates of endoscopic remission were higher in the biologic-naive (50.5%)]

My take: In addition to ustekinumab (already approved), a number of other therapeutic agents that target IL-23 are likely to be available soon to help manage Crohn’s disease. This includes risankizumab but others with phase 3 studies include brazikumab, mirikizumab, and guselkumab..

Slide from David Rubin Twitter Feed (March 2021). Ozanimod now approved.

Ustekinumab vs Adalimumab: Head-to-Head Study

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From Gastroenterology & Endoscopy News: Head-to-Head Trial Shows Similar Efficacy and Safety With Ustekinumab and Adalimumab

An excerpt:

The first head-to-head trial comparing ustekinumab and adalimumab has found the two drugs are similarly safe and effective in patients with moderate to severe Crohn’s disease…

Dr. Scherl and her co-investigators in the SEAVUE trial randomly assigned 386 biologic-naive patients with Crohn’s disease to receive one year of treatment with either ustekinumab or adalimumab at standard on-label doses, with no dose escalation throughout the study period and no concomitant immunomodulators...

The findings, which were presented at the 2021 annual meeting of the European Crohn’s and Colitis Organisation (oral presentation OP02), showed that after one year of treatment, 65% of patients who received ustekinumab and 61% of those who received adalimumab achieved clinical remission, defined as a CDAI below 150...[And] similar additional outcomes, including clinical response at one year (72.3% for ustekinumab vs. 66.2% for adalimumab), corticosteroid-free remission at one year (60.7% vs. 57.4%, respectively), endoscopic remission at one year (28.5% vs. 30.7%) 

My take: This study indicates that ustekinumab likely has similar safety and efficacy as adalimumab (though the study did not allow dose escalation or immunomodulators); thus, it could be positioned as a first-line treatment. It is administered less frequently as well.

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Is An Unproven Medication Worth More Than the EPA or NASA?

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For those who have not followed the FDA’s controversial decision of approving Aducanumab for the treatment of Alzheimer’s disease, the NEJM has two useful commentaries:

Key points -from 1st article:

  • “Biogen…has announced a list price of $56,000 –10 times the evidence-based benchmark recommended by the independent Institute for Clinical and Economic Review…if even 10% of U.S. patients with Alzheimer’s disease were prescribed aducanumab, drug spending for Medicare Part B would increase from $37 billion to $69 billion per year”
  • The authors note that Medicare Part B payments rely on average sales price (ASP) from private insurers rather than a direct negotiated price; thus, the higher the price for private plans (even if poorly covered), the higher the Medicare rate
  • Hospitals and physicians are incentivized at higher prices due to receiving a 4-6% reimbursement price over the acquisition price
  • “The $56,000 price for aducanumab is a rational manufacturer response to an irrational insurance system.”

Key points -from 2nd article:

  • By one estimate, the potential cost will exceed the budgets of agencies such as EPA or NASA
  • “In granting accelerated approval to aducanumab, the FDA concluded that the drug’s ability to reduce amyloid plaques was reasonably likely to translate into clinical benefits. But this claim is hotly contested and was not presented to the FDA’s advisory committee, which voted against recommending approval of the drug because of the lack of a demonstrated clinical benefit”
  • If Medicare refuses to cover medication, this would leave a burden to state budgets. “As a legal matter,…state Medicaid programs are required to cover nearly all FDA-approved drugs.”
  • “Congress could adopt new legislation specifying that state Medicaid programs need not cover aducanumab…Protecting state budgets shouldn’t require Medicare to cover an expensive drug with unproven clinical benefits.”

My take: This type of huge fiscal burden may provide the rationale for Medicare and Medicaid to reexamine whether/how they cover expensive FDA-approved medications.

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NASPGHAN Toolbox App

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Patrick Reeves passed along the following helpful information about the NASPGHAN toolbox:

The NASPGHAN Fellows committee, working in close partnership with the NASPGHAN Technology and Training committees, has developed an App named, “The NASPGHAN Toolbox”.

The App is equipped with ready access to: clinical calculators, guidelines and algorithms, medication guides, patient education resources, and more. You can access the Toolbox via its URL (https://toolbox.naspghan.org/) on your phone or computer.

The NASPGHAN team hopes this will enhance your day-to-day patient care of children with gastrointestinal disorders.

Some highlights:

Some screenshots:

Genetic Basis of Eosinophilic Esophagitis

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Cincinnati Children’s Research Horizons: Two Genes Associated with Familial EoE

Researchers (first author Tetsuo Shodaand senior author Marc Rothenberg) at “Cincinnati Children’s have identified two rare gene variants associated with inherited forms of eosinophilic esophagitis (EoE) that may also play roles as acquired mutations among the larger population of people with non-familial EoE.”  

Citation of article: Shoda, T., Kaufman, K.M., Wen, T. et al. Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis. Nat Commun 12, 6795 (2021). https://doi.org/10.1038/s41467-021-26939-9

The findings regarding the genes desmoplakin (DSP) and periplakin (PPL) were published Nov. 23, 2021 in Nature Communications (Link to article: Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis). “The proteins generated by these genes are found in the epithelial layer of the esophagus amid structures called desmosomes that help bind cells together. These variants of DSP and PPL appear to weaken the epithelial barrier, making the tissue more prone to damage from inflammation-causing eosinophils.”

Methods: Using whole-genome sequencing, the researchers discovered the variants among five members of a family that had multiple generations of members with EoE.  The team tested another 61 families with familial EoE and found 13 having either the DSP or PPL variants.

Key Findings:

  • The authors “estimate that these gene variants account for about 21% of patients with familial EoE”
  • “A series of functional analyses using an organotypic-like ALI culture system demonstrated that modulating wild-type DSP and PPL expression in vitro was functionally sufficient to induce changes in epithelial integrity (e.g., acantholysis) and barrier impairment, processes that are dysregulated in EoE”
  • “DSP and PPL loss occurs in non-familial EoE, substantiating that the pathway identified initially by rare familial EoE cases is broadly applicable to familial and non-familial EoE”

My take:

  1. This article provides data showing that genetic alterations affecting the epithelial barrier are important in the pathophysiology of EoE.
  2. Often EoE is compared to eczema. This finding of altered epithelial barrier is analogous to eczema where many cases are due to a mutation in a protein called filaggrin, which is important in reducing the gap between skin cells (related blog: Eczema Rarely Linked to Food Allergy).

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Ongoing Hepatitis B Susceptibility in U.S. Adults

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H Roberts et al. Hepatology 2021; 74: 2353-2365. Prevalence of HBV Infection, Vaccine-Induced Immunity, and Susceptibility Among At-Risk Populations: US Households, 2013-2018

This article provides some useful trends in Hepatitis B virus (HBV) epidemiology based on NHANES surveys (National Health and Nutrition Examination Survey).  Persons who tested negative for anti-HBc, HBsAg, and anti-HBs were considered susceptible to HBV infection.

Key Findings:

  • The estimated prevalence of persons living with chronic hepatitis B in the USA has remained unchanged at 0.3% since 1999. During 2013-2018, this accounted for 880,000 US residents who were living with chronic HBV infection. It is noted that only a minority of the 11.7 million residents with a history of HBV develop chronic HBV
  • The non-US-born population accounted for 69% (610,000) of persons living with chronic HBV and 70% of this group were Asian. Non-US born population had a 9-fold risk of chronic HBV compared to US-born persons
  • Among adults aged ≥ 25 years who resided in US households, an estimated 155.8 million persons (or 73.4%) were susceptible to HBV infection. Susceptibility was lower in the 25-49 age group (64.8%) compared to the 50 years and older group (81.6%)
  • Despite vaccine recommendations, at risk groups including those using illicit drugs, hx/o MSM, and HCV exposure continue to have high susceptibility; fewer than 25% of adults “deemed to be at high risk for contracting HBV infection had vaccine-induced immunity
  • Overall, vaccine-induced immunity increased to 21.4% (2013-2018) compared to previously 17.9% (2007-2012) in those 25 years and older
  • Limitations: lack of detectable anti-HBs is likely to overestimate susceptibility in those who have previously been vaccinated, participation in NHANES by non-US born persons may have been unequal, and determining timing of HBV acquisition by non-US born persons was not feasible in this study

My take: Lots of adults have chronic HBV and lots more are susceptible. How to identify and encourage adults to avoid vaccine-preventable illnesses is NOT getting easier.

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From NPR 12/5/21

Frequency of Strictures in Pediatric Eosinophilic Esophagitis

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D Burnett et al. JPGN Reports 2021; Free Access: Incidence of Pediatric Eosinophilic Esophagitis and Characterization of the Stricturing Phenotype in Alberta, Canada doi: 10.1097/PG9.0000000000000136

This retrospective study (2015-2018) identified 185 new cases of eosinophilic esophagitis (EoE).

Key findings:

  • Eight of 185 (4%) patients had endoscopically confirmed esophageal strictures, 4 of which required mechanical dilation. (The authors note a Dutch study which demonstrated a 14% stricture rate)
  • Eleven of 185 (5.9%) patients had more subtle signs of esophageal narrowing, but no focal strictures
  • Pain was reported after 15% of all scopes, including 50% of the 28 scopes with focal strictures
  • For patients <15 years old living in Edmonton, the incidence over the 4 years was 11.1 cases per 100,000 person years
  • EoE was more common in urban setting: incidence 10.6 versus 4.1 per 100,000 person-years, respectively

My take: This article provides useful data on the likelihood of stricturing EoE in the pediatric population in an area with a high incidence of EoE.

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