Category Archives: Pediatric Gastroenterology Intestinal Disorder

“Genetic Testing and the Future of Pediatric Gastroenterology”

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Last night, a symposium on “Genetic Testing and the Future of Pediatric Gastroenterology” sponsored by Children’s Healthcare of Atlanta took place.  The speakers included Dr. Ben Gold from our pediatric GI group (GI Care for Kids), Dr. Saul Karpen and Dr. Subra Kugasthasan (Emory), and Dr. Robert Heuckeroth (CHOP).

This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.  All of the speakers had terrific presentations.

GI Genetic Testing –Subra Kugathasan

Reasons for genetic testing:

  • Predicting prognosis: predicting stricturing/fibrosis in Crohn’s, predicting cancer in ulcerative colitis; BRCA1 in breast cancer
  • Choosing the right medicine: pharmcogenomics
  • Precision medicine: prevention of disease, slowing progression of disease.

Examples in current medicine:

  • Recurrent pancreatitis –novel mutations identified in SPINK1.  Also now hereditary pancreatitis may be due to mutations in CPA1, GGT1, CLDN2, MMP1, MTHFR in addition to CTRC, SPINK1, CFTR, and PRSS1.
  • Inflammatory bowel disease (IBD):IL10 Receptor mutation , TTC7A –>VEO IBD; IPEX gene (can worsen with immunosuppression). Panel testing now available for 40 genes –4 of 22 patients identified with IBD.  Identifying cause of VEO IBD may lead to treatment: bone marrow transplantation.
  • IBD: CLIA/CAP certified Emory Genetics panel ~50 genes (genetics.emory.edu/egl/tests/view.php?testid=4420). Dr. Kugathasan indicated that this testing is likely to be a better 1st step then exome testing. Yield with exome sequencing (in highly selected populations) about 25% at this time but likely to increase. If negative, can proceed with whole exome sequence.  Numerous problems with exome sequencing; for example, exome sequencing may identify genes of unknown significance and identifying genetic problems unrelated to clinical issue.

Who/When to test?

  • Very early onset disease (<10 years), atypical presentation, perhaps treatment-refractory.

Take-home point: “All GI diseases have genetic testing in future.” Testing for highly selected patients for gene defects can be accomplished with gene panel and if negative, whole exome testing.

Related blog posts:

Liver: Cholestatic & Metabolic Diseases of Infants and Children —Saul Karpen

Potential areas for genetic testing:

  • Neonatal cholestasis: PFIC, Metaboic, Biliary Atresia
  • NAFLD
  • Transplant

“Why bother…they all get transplanted anyway…”  According to Dr. Karpen, this view needs to be reconsidered.

Neonatal cholestasis:

  • (Front Pediatr 2014; 2: 65)  41% with biliary atresia, 13% idiopathic, and a lot of others.  N=82. Other etiologies: Genetic disorders; Biliary disease (eg. Caroli), transporter defects (PFICs/BRICs), Metabolic (Niemann-Pick C, tyrosinemia, HFI, Peroxisomal, GSDs, Peroxisomal, Mitochondrial, A1AT). Thus, panels to identify these disorders can be very helpful.
  • Emory Cholestasis 56+ Gene Panel. Testing is cheaper than endoscopy

PFIC: Progressive Familial Intrahepatic Cholestasis

  • PFIC1: ATP8B1 (Byler) –besides cholestasis, patients often with diarrhea, hearing loss, very itchy; can have cirrhosis at 2 years of life
  • PFIC2: ABCB11 (BSEP deficiency) –can have cirrhosis at 6 mo, prone to HCC (as early as 13 mo), very itchy
  •  PFIC3 (high GGT) ABCB4 –can have cirrhosis at 5 mo, can cause problems at later ages as well (eg. intrahepatic cholestasis of pregnancy, gallstones); increase risk for HCC/cholangiocarcinoma.
  • Identifying PFIC (could mimic PSC) and BRIC (Benign Recurrent Intrahepatic Cholestasis)–is helpful in following patients for specific management when symptoms recur and to screen for complications (eg. HCC).

Biliary Atresia:

  • No clear genetics in most
  • Laterality defects in 5-10% -asplenia/polysplenia, cardiac defects
  • GPC1 gene is a susceptibility gene in zebrafish
  • ADD3 gene identified in Han Chinese OR 2.38 –may be a susceptibility gene. (30% of cases, 17% of controls)

NAFLD: Associated with increased mortality compared with matched controls. Patients develop thicker atherosclerotic plaques. PNPLA3 gene identified as a susceptibility gene for NAFLD and is highly prevalent in Hispanic populations.  Similarly, PNPLA3 has been associated with NASH in Italian populations.  If you have this genotype, this increases risk of liver fat in the face of increased sugar consumption.

Transplant medicine: Deoxyguanosine Kinase Deficiency (DGUOK) –rapid sequencing for this gene pretransplant –If positive, should not be transplanted. These individuals have systemic disease that cannot be cured with liver transplantation.

Who/When for genetic testing?: DGUOK in liver failure patients, and in infants without diagnosis after liver biopsy/exclusion of A1AT

Take-home message: Genetic testing has a role in pediatric liver disease and it is affordable.

Related blog posts:

GI –Single Microbes to the Microbiome and GI Disease —Ben Gold

  • Described why changes in our environment can trigger development of disease due to changes in microbiome (eg. immigrants/children with IBD in developed countries at much higher rate than at developing countries)
  • Discussed Helicobacter pylori –‘how a single microbe which may have been good turned bad’
  • Described pathogenesis. What you get exposed to early on may lead to an exaggerated response by T-cells/immune system.  Healthy microbiota is critical to train the immune system via GALT to protect host and decrease the chances for immune overexpression.

Key points:

  • 100 trillion bacteria that live in our GI tract. 10x number of human cells in our body and 100x as many genes as there are in the human genome.  Partnership between humans and their microbiome developed over thousands of years.
  • Vaginal delivery is NOT sterile. Are there consequences to C-section? Food allergy for infant –OR 2.5 if Mom with food allergy delivers vaginally vs OR 7.8 if Mom has food allergy and delivers via C-section. Also, some data indicates increased risk of EoE if born via C-section.  From DAY 1, microbiome can be influence by environmental factors.
  • Influencing microbiome happens mainly during first three years of life.

Why the microbiome is so important/more pointers:

  1. Since 1950, there has been a huge decline in infectious diseases like measles, mumps, hepatitis A, tuberculosis, etc
  2. Coincident with these decreases there has been increased multiple sclerosis, Crohn’s disease, asthma, food allergy, autoimmune diseases
  3. Sanitized food supply, decrease in naturally fermented foods, urban lifestyle, antibiotics, C-section all lead to lower microbial exposure and altered intestinal microbiota. This in turn may lead to an inadequate immune response.
  4. Elie Metchnikoff 1845-1916: suggested ingested bacteria could be healthy. Probiotics/prebiotics are not a new idea!
  5. Obese patients had very high levels of Firmicutes and low Bacteroidetes.
  6. Fecal microbial transplantation (FMT)–reseeding GI microbiome. FMT may be beneficial to many diseases and is being  studied.

Helicobacter pylori -evidence of H pylori as far back as 60,000 years ago and has evolved with humans. H pylori may have helped provided a positive immune response in children and adults.

Bottomline: Human genetic diseases may be heavily influenced by the 300 trillion bacteria and their genes; these bacteria are susceptible to environmental disease.

Related blog posts:

 

Genetic Basis of Motility —Robert Heuckeroth

  • Basic machinery controlling motility described –enteric neurons, muscles, pacemaker cells.
  • Very little clinical overlap between modern genetic testing and applicable motility disorders: achalasia, gastroparesis, pseudoobstruction, Hirschsprung’s or irritable bowel
  • Focused testing for suspected diagnosis is being displaced by broader testing in serious disease, especially since more extensive genetic testing may be more cost-effective. When to do exome sequencing?

Hirschsprung’s disease:

  • 1:5000 children.
  • 100X higher risk in Down Syndrome.
  • Prenatal testing not helpful at this time. There may be >360 genes that increase risk (variable degree of risk) of Hirschsprung’s disease; hence prenatal testing not that helpful at this time.
  • 30 associated genetic syndromes with Hirschsprung’s, >12 known gene defects.  Hirschsprung’s disease: 25% with RET haploinsufficiency.  RET haploinsufficiency –increases risk of Hirschsprung’s disease >2500-fold risk.
  • Gene environment interactions can increase risk of developing Hirschsprung’s disease –if vitamin A deficient, mice with increased risk.
  • RET gene –>too little RET increases risk of Hirschsprung’s
  • RET gene –>too much RET increases risk of MEN2B, MEN2A.  Though 7.5% of MEN2A have Hirschsprung’s –works out to be 1 in 100 kids with Hirschsprung’s have MEN2A mutations.  ??test for this??

Pseudoobstruction genetic basis– a number of genes identified, including ACTG2 (smooth muscle actin gene).  If you understand etiology, this may lead to prevention and treatment.

Take-home message: Currently biggest problem with genetic testing, especially with motility disorders, is identifying genetic defect of unknown significance.  Thus, testing needs to be done as part of research studies.

Related blog posts:

 

 

 

Link to NASPGHAN Lectures and Postgraduate Course

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Later this week, our national pediatric GI meeting (North American Society for Pediatric Gastroenterology Hepatology and Nutrition) is starting in Atlanta.  Many in my group are involved and presenting.

The following link (with permission from NASPGHAN) is to the website with links to all of these lectures:

NASPGHAN 2014 Atlanta meeting

For those interested only in the Syllabus for the Postgraduate Course:  NASPGHAN 2014 Postgraduate Course.

Topics include in this 200 page (online) book: primary sclerosing cholangitis, jaundiced infant, acute liver failure, “dreaded” endoscopy wake up calls, endoscopy for biliary tract disease, extraesophageal manifestations of gastroesophageal reflux, constipation, eosinophilic esophagitis, motility disorders, FODMAPs diet, nutrition for neurologically impaired, early onset inflammatory bowel disease, “luminitis” due to non-IBD causes, new IBD treatments, and diet-microbiome.

Should be great!

Also, to plan your meeting -go to NASPGHAN home page and use mobile guidebook: NASPGHAN 2014 has gone mobile using Guidebook!

Anti-TNF Therapies: Safe in Pregnancy

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According a review (Inflamm Bowel Dis 2014; 20: 1862-69) of 5 studies with 1216 patients, “the use of anti-TNFα therapy does not seem to increase the risk of unfavorable pregnancy outcomes among women with IBD, although the optimal timing of therapy through pregnancy and the postpartum period was not assessed.”

Other important points:

  • “Current recommendations suggest that anti-TNFα therapies be continued during the first 2 trimesters of pregnancy.”  Withholding of infliximab and adalimumab during the third trimester is due to concerns of increased drug levels in infants.
  • Live virus vaccination should “be avoided for the first 6 months in children who had exposure to anti-TNFα therapies in utero.”

Related blog posts:

IBD in Ontario: 1 in 200

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A recent study notes an increasing incidence of and high prevalence of inflammatory bowel disease (IBD) in Ontario, Canada (Inflamm Bowel Dis 2014; 20: 1761-69).

This article notes that between 1999-2008, there was an increased incidence of IBD from 21.3 to 26.2 per 100,000.  This affected most age groups less than 65 years, but increased most rapidly in children younger than 10 years (increased 9.7% per year).  The highest incidence remained in adults aged 20 to 29 years. The overall prevalence in Ontario was estimated to be 1 in 200 overall, which is among the highest in the world.  This study relied on a validated health administrative data consisting of all Ontario residents.

The potential for misclassification bias is discussed and the potential difficulties with administrative health data is detailed in three related editorials (pages 1777-79, 1780-81, 182-83).  The editorials are helpful, in part, because a separate study in the same journal (Inflamm Bowel Dis 2014; 20: 1770-76) indicates that the incidence of Crohn’s disease and Ulcerative Colitis declined in Quebec between 2001-08. However, the authors of this study used less-rigorous methods and had a much shorter “washout” period (two years versus eight years).

At the end of the day, with conflicting studies, there remains some uncertainty with regard to IBD epidemiology.  That being said, the first study notes that “75% of CD studies and 60% of UC studies had reported increased incidence in the adult populations.”

This leads back to the question of what environmental exposures are leading to these changes in incidence.

Bottomline: This article and the associated editorials helps highlight the difficulties of using administrative health data and why many data points are needed to assess the epidemiology of IBD.  In all likelihood, the incidence of IBD is increasing.

Related blog post: Global increases in IBD incidence | gutsandgrowth

 

How to Protect Children From Celiac Disease

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While many parents have asked what they can do to protect their children from celiac disease, the new answer will be more limited than in the past.  Two recent studies from NEJM indicate that timing of gluten introduction and breastfeeding do not appear to significantly influence the development of celiac disease.

Here are the links:

1st Study: Introduction of Gluten (6 months vs 12 months)

  • Results: (n=707) At 5 years of age, the between-group differences were no longer significant for autoimmunity (21% in group A and 20% in group B, P=0.59) or overt disease (16% and 16%, P=0.78 by the log-rank test).
  • CONCLUSIONS: Neither the delayed introduction of gluten nor breast-feeding modified the risk of celiac disease among at-risk infants, although the later introduction of gluten was associated with a delayed onset of disease. A high-risk HLA genotype was an important predictor of disease.

2nd Study: Gluten 16-24 weeks or Delayed  n=944

  • CONCLUSIONS As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children.

Here’s a story from Boston Globe summarizing findings: Tactics to Prevent Celiac

Bottomline: These well-designed studies argue persuasively against the previously held views that breastfeeding and timing of gluten introduction influence the development of celiac disease.

Related blog posts:

NASPGHAN Educational materials for medical professionals –NASPGHAN Celiac Link

Another Look at Gluten-free Diet for Asymptomatic Celiac

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Previously, a blog entry (Benefits of Gluten-Free Diet for “Asymptomatic” Celiac …) reviewed the abstract (available early online) from Gastroenterol 2014; 147: 610-17.  With the publication of the printed version, some useful commentary (Gastroenterol 2014; 147: 557-59) provides perspective.

Study limitations: small number (20 assigned to gluten-free diet, 20 regular diet).

Key points from editorialists:

  • “This study provides some of the strongest data yet supporting celiac disease screening of family members of patients with celiac disease.  However, important issues must be addressed before screening is widely adopted.”
  • “This [study] leaves us in the uncomfortable position of offering a diagnosis that may improve gastrointestinal symptoms, but simultaneously worsen socialization, offer limited overall change in health-related quality of life, and for which the long-term risk-to-benefit ratios are unknown.”
  • This “makes the cost of a gluten-free loaf of bread for all with asymptomatic celiac disease too high, unless and until additional more substantial benefits can be demonstrated.”

Related blog posts:

Sweet Alternative to Splenda for Budesonide

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A recent article (JPGN 2014; 59: 317-20) has shown that Neocate Nutra is a good alternative to splenda as a delivery vehicle for budesonide for children with eosinophilic esophagitis.

This retrospective review of 60 children treated with oral viscous budesonide (OVB) who used either splenda (n=46) or with Neocate Nutra (n=14).  With regard to budesonide, in patients less than 10 years, the dose was 1 mg/day and older children received 2 mg/day.  For splenda patients, 10 packets were used to create a slurry whereas with Neocate Nutra powder the amount was 2.5 cm3 per milligram of budesonide.  Followup endoscopy took place at least 10 weeks after the start of treatment.

Key findings:

  • 13 of 14 Neocate Nutra patients achieved a histologic response (peak eosinophils <15/hpf) compared with 30 of 46 Splenda patients.
  • Mean eosinophil count dropped from 62 to 9 for Neocate Nutra patients and from 59.5 to 25.5 for Splenda patients.

Limitations of study: small number, retrospective study.

Take-home message: Neocate Nutra is at least as effective as Splenda as mixture with budesonide.  In addition, many parents may prefer to avoid Splenda.

Related blog posts:

Four Food Group Diet for Adults with Eosinophilic Esophagitis

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A recent study published online (here’s a link: EoE 4-food Group Diet) shows that a four food elimination diet was effective in 54% of the adults in this study.  Here’s the abstract:

Background

Eosinophilic esophagitis (EoE) is an esophageal disorder predominantly triggered by food antigens. A six-food group elimination diet (SFGED) achieves remission in more than 70% of adult patients with EoE. After individual food reintroduction, just 1 or 2 food triggers for EoE can be identified in 65% to 85% of the patients, so some dietary restrictions and endoscopies after food challenge may be unnecessary.

Objective

To evaluate the efficacy of a four-food group elimination diet (FFGED) (dairy products, wheat, egg, and legumes) for adult patients with EoE.

Methods

Prospective multicenter study. All patients were reevaluated after 6 weeks on an FFGED. Response to the FFGED was defined by clinical and histologic (<15 eos/hpf) remission. Responders underwent reintroduction of each individual food over 6 weeks followed by endoscopy and esophageal biopsies. Nonresponders were offered a rescue SFGED.

Results

A total of 52 adult patients were included, of whom 12 patients (23%) had previous failure to topical steroid therapy. Twenty-eight of the 52 patients (54%) achieved clinicopathologic remission on the FFGED and 6 of the 19 (31%) nonresponders to the FFGED were successfully rescued with the SFGED. Twenty-two of 28 responders to the FFGED (78%) finished the individual food reintroduction challenge. Milk was identified as an EoE trigger in 11 patients (50%), egg in 8 (36%), wheat in 7 (31%), and legumes in 4 (18%). All patients had just 1 or 2 food triggers, with milk being the only causative food in 27% of the patients.

Conclusions

An FFGED achieved clinicopathologic remission in 54% of adult patients with EoE. An SFGED was effective in almost a third of FFGED nonresponders, resulting in a combined efficacy of 72% of both strategies.

Related blog post:

What is the Role for Allergy Testing in Eosinophilic Esophagitis?

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A recent review article (Clin Gastroenterol Hepatol 2014; 12: 1216-23) summarizes the potential role of allergy testing for eosinophilic esophagitis (EoE).

The article summarizes the potential ways to use various allergy testing and reviews the literature on its effectiveness.  The article notes a couple of key points:

  • Overall, using skin prick testing (SPT) and atopy patch testing (APT), allergy testing has not proved more reliable then empirically administering a 6-food elimination diet.  Thus, “the issue remains whether food allergy testing provides a useful tool in EoE.” However, targeted testing-based diets (especially in children) may require elimination of fewer foods.
  • “Serum IgE food-specific IgE panels should not be used for EoE.”  “Testing for foods, especially IgE testing, leads to recognition of food sensitizations that may not be clinically relevant and that on elimination, could result in the loss of tolerance to the food.”
  • Testing for milk allergy is noted have a high false negative rate.
  • IgG based testing is not recommended.  In fact, IgG immunoglobulins are “associated with tolerance rather than allergy.”
  • “Only 8% of children will become tolerant to all foods that cause their EoE.”

Bottomline: While foods commonly triggers EoE, the tests to identify these foods are far from perfect. I find that families are quite uninformed about the frequent lack of correlation between allergy testing and true EoE triggers.

Related blog posts:

Summary of article: GI & Hepatology News August 2014 Role of Allergy Testing in EoE

Elimination Diets for Eosinophilic Esophagitis in Adults

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A recent study shows that elimination diets, including a six-food group elimination diet (SFED) can be effective in adults with eosinophilic esophagitis (EoE) (Clin Gastroenterol Hepatol 2014; 12: 1272-79).

This retrospective study identified 31 adults (mean age 36 years) who underwent dietary therapy between 2006-2012.  22 had a targeted elimination diet (TED) and 9 had SFED.

Key findings:

  • Symptoms improved in 71% (68% TED, 78% SFED)
  • Endoscopic appearance improved in 54% (53% TED, 56% SFED)
  • 39% had eosinophil count drop below 15 eos/hpf (32% TED, 56% SFED).  Overall in the entire cohort, mean eosinophil count dropped from 78 eos/hpf at baseline to 43 dos/hpf.
  • Among the nine responders with food reintroduction, the most common foods identified as triggers (using food reintroduction) were milk (4), egg (4), wheat (2), shellfish (1), and legumes (1).