Author Archives: gutsandgrowth

Unknown's avatar

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.

Putting in Place a Big Piece of the Eosinophilic Esophagitis Puzzle

Posted on by

A recent study (Nature Genetics 2014; doi:10.1038/ng.3033 -thanks to Seth Marcus for this reference) provides novel in-depth molecular and mechanistic information on eosinophilic esophagitis (EoE).  Though the publication and supplemental material span only 8 pages, it is packed with information and highly technical assays and thus takes an effort to work through.

The authors performed a genome-wide association study (GWAS) of SNPs (single nucleotide polymorphisms) from >1.5 million genetic markers.  In total, this study involved samples from 736 EoE patients and 9246 controls. Four prominent markers were identified at 2p23, 5q22, 8p23, adn 15q13; however, the marker at 2p23 was most highly associated with a risk for EoE.  And, 2p23 included the CAPN14 gene (best SNP rs77569859).

Key Results:

  • CAPN14 is “specifically expressed in esophageal epithelium and is dynamically upregulated as a function of disease activity.”  Though CAPN14 is expressed in other tissues, it is primarily in the esophagus and pharynx (Figure 2).
  • CAPN14 encodes calpain 14, a calcium-activated cysteine protease.  CAPN14 showed the greatest upregulation in comparison to all members of the CAPN family.  Calpain proteases mediate protein cleavage for structural proteins, signaling molecules, transcription factors, and inflammatory mediators.  The latter are “germane for allergic responses.”
  • CAPN14 levels are >2-fold increase in individuals with active EoE.
  • CAPN14 gene is modified by IL-13.

Take-home message: (from the authors) This study shows the “potential centrality of CAPN14 in the etiology of EoE….We propose a model that links the interplay of allergic sensitization with an EoE-specific, IL-13-inducible esophageal response involving CAPN14.”

Related blog posts:

 

 

Web is Better: Liver Toxicity from Herbs

Posted on by

A recent review article (Clin Gastroenterol Hepatol 2014; 1069-76) provides a good overview of herbs and liver injury; however, the NIH website http://livertox.nih.gov/ is more comprehensive.

The article notes the difficulty in assessing liver injury from herbs and dietary supplements due to the permissive regulatory environment and underreporting.

Specific products reviewed include the following:

  • Weight loss supplements: hydroxycut, herbalife, green tea, usnic acid
  • “Health-promoting” herbs: black cohosh, comfrey, kava
  • Joint health supplements: flavocoxid, glucosamine
  • Bodybuilding supplements: anabolic steroids

The article explains issues with regard to causality and the regulatory issues. However, for each of these products, I found them on the livertox website. So, that is where I would start if I needed to look up herb-induced liver injury.  Reporting of adverse events can occur through FDA website: http://www.fda.gov/safety/medwatch/default.htm or through hotline: 800-FDS-1088.

A related reference –Bad Way to Lose Weight: “SlimQuickTM-Associated Hepatotoxicity Resulting in Fulminant Liver Failure and Orthotopic Liver Transplantation” ACG Case Rep J 2014;1(4):220–222. http://dx.doi.org/10.14309/crj.2014.59. Published: July 8, 2014

Related posts:

A New Villain for Hepatitis C

Posted on by

A recent article (Hepatology 2014; 59: 2403-12) notes a changing perception for Hepatitis C (HCV) genotype 3.  Previously, HCV genotype 3 was considered easy-to-treat with pegylated interferon and ribavirin.  Along with genotype 2, treatment for genotype 3 was given for half the duration as treatment for genotype 1; in addition, the response was much better than genotype 1 (~70-80% compared with ~50%).

With new treatments, the situation has changed.  In the U.S., genotype 1 accounts for about 70% of all infections and worldwide about 60% of all HCV infections.  In contrast, genotype 3 accounts for 10-15% of the world HCV reservoir.

Specific problems (alluded to by the authors) with genotype 3:

  • Increased steatosis
  • Increased liver fibrosis progression
  • Increased risk of hepatocellular carcinoma (HCC)
  • Increased risk of end-stage liver disease
  • Reduced sustained virological response (SVR) after direct-acting antiviral therapies

While the newest therapies have dramatically increased SVR rates for genotype 1 and improved treatment for genotype 2, this is not the case with genotype 3 thus far.  Instead of being a good genotype, genotype 3 is now a villain.

Another article provides additional data on HCV genotype 3 (Hepatology 2014; 60: 98-105).  In this study of U.S. Veterans with HCV (n=110,484), there were 8,337 with genotype 3.  In this group, despite being younger, they had a higher risk of cirrhosis (HR 1.40) and hepatocellular carcinoma (HCC) (HR 1.66) in comparison to HCV genotype 1.

Related blog posts:

 

Beauty is More Than Skin Deep

Posted on by

A recent article discusses how a British model is an inspiration.  “Bethany Townsend made a bold move posting photos of herself in a bikini with colostomy bags on full display….Millions of people have seen her picture on the Crohn’s and Colitis UK page.”

If you want, take a look; here’s the link: British bikini model 

Childhood Salmonella and Development of Irritable Bowel

Posted on by

“An analysis of children affected by a Salmonella enteritidis outbreak more than 20 years ago provides evidence that pathogen-induced gastroenteritis during childhood is a risk factor for irritable bowel syndrome (IBS) in adults. The findings from this long-term study are published in the July issue of Gastroenterology.”  This study (Gastroenterol 2014; 147: 69-77) is nicely summarized in a recent AGA Journal blog –here’s the link: What are the Long-Term Effects of Gastrointestinal Infections During Childhood.

Key point/excerpt:

Cesare Cremon et al. identified and monitored individuals affected by a foodborne Salmonella enteritidis outbreak that involved 1811 people in Bologna, Italy in 1994. The outbreak resulted from delivery of contaminated tuna sauce to 36 schools. Although some adult staff became ill, 93% of those affected were children, 3–10 years old…Sixteen years later, Cremon et al. evaluated the long-term effects of the outbreak, mailing a questionnaire to 757 subjects…Among exposed participants, 32.3% reported functional dyspepsia, compared with 27.1% of controls, and 36.8% reported having IBS, compared with 23.3% of controls. The odds ratio for IBS among people exposed to the Salmonella was 1.92.

Omega-3 Fatty Acids, Lipid Emulsions, and Hepatic Pathology

Posted on by

Many have advocated for the use of parenteral fish oil lipids like Omegaven which are rich in omega-3 polyunsaturated fatty acids (O3FAs), though the data in support of them are limited (New lipid emulsions — lacking data to support usage …).

A recent study (J Pediatr 2014; 165: 59-64) identified seven liver-inclusive intestinal transplants who had received O3FAs.   This retrospective review study took place between 2003-2012.  These seven patients had received O3FAs for a mean of 62% of their total life span before transplant.  While these patients almost all had resolution of cholestasis (mean total bilirubin 0.7 mg/dL at time of transplant), advanced fibrosis (stage 3 or 4) was noted on explant pathology.  The histologic inflammatory scores were lower (P=.056) in comparison to O6FA group.

The authors make several important points:

  • The “results provide additional evidence that the improvement in hyperbilirubinemia following O3FA substitution therapy does not consistently produce histologic recovery of the liver.”
  • This study does not address whether comparable improvements could have been obtained from lipid restriction among the O6FA group.
  • Only 1 of 20 studies of O3FA lipid emulsion in PNALD includes hepatic histopathology as an outcome measure.

This is not the first study that indicates that liver fibrosis may persist and progress on O3FA therapy (J Pediatr 2010; 156: 327-31, J Pediatr Surg 2010; 45: 95-9, JPGN 2013; 56: 364-9).

Bottomline: Continued investigation of O3FA emulsions in PNALD is needed and assessing liver histology may be needed prior to intestinal transplantation.

Related blog posts:

 

Systemic Review of Dietary Treatments for Eosinophilic Esophagitis

Posted on by

A recent analysis of the literature for dietary treatment of eosinophilic esophagitis (EoE) has been published (Gastroenterology 2014; 146: 1639-48). Only 33 references out of 581 screened were included, yielding 1317 patients (1128 children and 189 adults).

Key findings:

  • Elemental diets were effective in 90.8%
  • Six-food elimination diets were effective in 72.1%
  • Allergy test-directed diets were effective in 45.5%
  • Adults responded similarly to children to dietary interventions with remission in 67.2% compared to 63.3%.

Bottomline: This study reiterates the dietary response rates from multiple previous studies. The finding that adults respond similar to children is less well-recognized, perhaps because dietary treatments are used less often in adults with EoE.

Related blog entries:

Tofacitinib -Risks and Benefits in Rheumatoid Arthritis

Posted on by

Previously Tofacitnib, an oral Janus kinase inhibitor, has shown promise as an emerging treatment for inflammatory bowel disease (Tofacitinib –a JAK Inhibitor for UC | gutsandgrowth).  So, a recent large study in tofacitinib use in rheumatoid arthritis caught my attention, specifically with regards to the potential risks of treatment (NEJM 2014; 370: 2377-86).

This double-blind study randomly assigned 958 patients (mean age ~49 years) to receive 5 mg or 10 mg of tofacitinib twice daily or weekly methotrexate.  This study, called ORAL Start, examined the effectiveness of these drugs over a 24 month period in patients with active moderate-to-severe rheumatoid arthritis naive to therapeutic doses of methotrexate.

Key findings:

  • Among tofacitinib patients, 25.5% (5 mg group) and 37.7% (10 mg group) had an ACR 70 response at 6 months compared with 12.0% of methotrexate patients.  Results at 12 and 24 months were similar (Figure 1)
  • Adverse effects:
  1. 4% of tofacitinib patients developed herpes zoster compared with 1.1% of methotrexate patients
  2. 5 tofacitinib patients developed cases of cancer (three cases of lymphoma) compared with 1 case among patients receiving methotrexate
  3. Tofacitinib was associated with decreases in neutrophil/lymphoctye counts, increases in creatinine levels, increases in aminotransferases, and increases (16-22%) in LDL/HDL cholesterol levels
  4. Four deaths were noted among patients treated with tofacitinib compared with none in the methotrexate patients.

Related blog post: Source Article: Methotrexate Safety | gutsandgrowth

Anti-TNF Agents in Pediatrics Have NOT Been Shown to Cause Lymphoma

Posted on by

This blog title is supported by a recent publication (Clinical Gastroenterology and Hepatology: http://dx.doi.org/10.1016/j.cgh.2014.01.021)

Here’s the abstract -(I emphasize a key point with bold) or check out the link above:

Background & Aims

Many physicians hesitate to recommend anti–tumor necrosis factor (TNF) therapy for pediatric patients with inflammatory bowel disease (IBD) because of concerns about risk of infection and cancer. We performed a systematic review to quantify the incidence of serious infection, lymphoma, and death among pediatric patients with IBD who received anti-TNF therapy. These values were compared with those expected from other treatments, from adults with IBD, and from the general pediatric population.

Methods

We searched MEDLINE, EMBASE, the Cochrane Collaboration, and Web of Knowledge for studies of infliximab therapy for children with ulcerative colitis or Crohn’s disease, or adalimumab therapy for children with Crohn’s disease. Standardized incidence ratios (SIRs) were calculated, comparing rates of infection and cancer among pediatric patients exposed to anti-TNF agents vs expected rates from pediatric patients not exposed to anti-TNF therapies or adult patients exposed to anti-TNF agents. Our analysis included 5528 patients with 9516 patient-years of follow-up evaluation (PYF).

Results

The rate of serious infections among pediatric patients treated with anti-TNF agents (352/10,000 PYF) was similar to that of pediatric patients who received immunomodulator monotherapy (333/10,000 PYF; SIR, 1.06; 95% confidence interval [CI], 0.83–1.36), but significantly lower than the expected rate for pediatric patients treated with steroids (730/10,000 PYF; SIR, 0.48; 95% CI, 0.40–0.58) or adults treated with anti-TNF agents (654/10,000 PYF; SIR, 0.54; 95% CI, 0.43–0.67). Five treatment-related deaths occurred (4 from sepsis and 1 from arrhythmia). Two patients developed lymphoma (2.1/10,000 PYF). This value was similar to the expected rate of lymphoid neoplasia in the entire pediatric population (5.8/100,000 PYF; SIR, 3.5; 95% CI, 0.35–19.6), and lower than the population of pediatric patients receiving thiopurine monotherapy (4.5/10,000 PYF; SIR, 0.47; 95% CI, 0.03–6.44), and among adults treated with anti-TNF agents (6.1/10,000 PYF; SIR, 0.34; 95% CI, 0.04–1.51).

Conclusions

Based on a systematic review, the risk of lymphoma was no greater among children with IBD who received anti-TNF therapy than those treated with other IBD therapies or adults treated with anti-TNF agents. The rate of serious infection was significantly lower among pediatric patients with IBD treated with anti-TNF agents than those treated with steroids, or adults with IBD who received anti-TNF therapy.

My take: This study shows that the concern for malignancy with anti-TNF agents (monotherapy) is often disproportionate to the true risk.  At the same time, much longer followup will be needed to assess the benefit and harm of these agents over decades.

Related blog posts:

 

 

 

 

 

 

Celiac Disease Risk -TEDDY Study

Posted on by

“The Environmental Determinants of Diabetes in the Young (TEDDY) is a multinational study that follows children at high genetic risk for type 1 diabetes, with the development of celiac disease as a secondary outcome.”  A recent publication provides excellent data with regard to the longitudinal risk of developing celiac disease (CD) (NEJM 2014; 371: 42-9).

Methods: 424,788 newborns were screened for at-risk HLA genotypes (from 2004 to 2010) in four countries (U.S, Finland, Germany, and Sweden).  21,589 had one of nine HLA genotypes of interest to the investigators –>8677 infants were enrolled in the study; 6403 of this group had one of the four HLA genotypes reported in this study:

  1. DR3-DQ2 homozygotes
  2. DR3-DQ2/DR4-DQ8
  3. DR4-DQ8 homozygotes
  4. DR4-DQ8/DR8-DQ4

Median follow-up: 60 months

Definitions for study:

  • Celiac autoimmunity: presence of tTG antibodies on two consecutive tests at least 3 months apart
  • Celiac disease: CD diagnosis based on biopsy (Marsh 2 or higher) or persistently high tTG (≥100 units) on at least two tests at least 3 months apart

Key findings:

  • Overall 786 children developed celiac autoimmunity (12%) and 291 had confirmed CD.
  • Children with DR3-DQ2 homozygosity had more than 5 times the risk of CD than the lowest-risk groups; in addition, the risk was 2.5 times more than the risk for a heterozygote (single DR3-DQ2) haplotype.
  • By 5 years of age, celiac autoimmunity developed in 26% and 12% respectively among children with DR3-DQ2 homozygosity  and in 11% and 3% of those children with DR3-DQ2 heterozygosity.
  • Residence in Sweden increased risk for CD with hazard ratio of 1.9.  The fact that residents with same genetic haplotypes had increased risk suggests that an environmental factor is playing a role.  It was noted that these children were given gluten-containing cereals at the earliest age.
  • CD was more common in females with HR of 2.16 (P<0.001) and in those with family history of CD HR 2.95 (P<0.001)

Take-home message: This prospective TEDDY study is providing useful information about how likely an individual with a genetic predisposition will develop CD and how quickly this develops.

Related blog posts: