How Genetics Influence Response to PPIs in Eosinophilic Esophagitis

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About two years ago, James Franciosi presented research at NASPGHAN meeting indicating that the main difference between children with eosiniophilic esophagitis (EoE) who respond to proton pump inhibitiors (PPIs) compared to those who do not was related to their metabolism of PPIs and not related to the nature of their underlying EoE.

Related blog: #NASPGHAN17 Eosionophilic Esophagitis Session

Now, more has been published on this topic: EB Mougey et al. JPGN 2019; 69: 581-7.

In this study with 92 patients, data was collected from participants in a prospective clinical trial of high-dose PPI for EoE.

Key findings:

  • 57 (62%) were responsive to PPIs and 35 (38%) were not responsive to PPIs
  • Carriage of STAT6 allele variant rs1059513 predicted responsiveness to PPIs with OR of 6.16
  • Carriage of STAT6 rs324011 synergizes with CYP2C19*17 to predict PPI-nonresponsive EoE

Discussion: 

  • Carriers of CYP2C19*17 are more likely to fail PPIs for EoE.  Children with CYP2C19*17 gain of function “have a 7.7 fold better odds of failing PPI therapy” than noncarriers.
  • CYP2C19*17 effects “appears to be exerted within a specific range of PPI doses…and does not appear to exert influence at the low and high ends of this dose range.”
  • STAT6, which in this study is a cofactor, “upregulates transcription of CCL26 (eostaxin-3) 53-fold in esophageal eosinophilia relative to levels in peptic esophagitis and 490-fold over levels found in normal esophageal biopsies.”
  • PPIs effectiveness “does not correlate with esophageal” acid exposure; thus, its effects are mediated via an anti-inflammatory mechanism.

My take: This study indicates that genotype-guided dosing of PPIs for the treatment of EoE is likely to be worthwhile.

 

View from Yonah Mountain, GA

How Bad is Reflux in Children with Esophageal Atresia?

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A recent retrospective study (FWT Vergouwe et al. JPGN 2019; 69: 515-22) with 57 children with esophageal atresia (EA) found most children have a normal reflux index.

This study, analyzing data between 2012-2017, reviewed all 24-hour pH-impedance (MII) studies in children at ≤18 months and 8 year olds with EA.  “All children with EA born in our hospital are offered a 24-hour pH-MII study at the age of 0.5 years and 8 years.”  In this institution, PPI treatment is given for at least 6 months after surgery. Of the 57 in the cohort, 20 had completed pH-MII at <18 months of age and 32 at age 8 years.

Key findings:

  • In children ≤18 months of age, median reflux index was 2.6% (abnormal in 2), median number of retrograde boluses was 61 (62% nonacid, 58% mixed)
  • In the older cohort (~8 years of age), median reflux index was 0.3% (abnormal in 4) and median number of retrograde boluses was 21 (64% nonacid, 75% mixed)
  • Overall, 10 of 57 children (17.5%) had GERD with reflux index >7% (n=6) or positive SI/SAP (n=4).  The authors note that much higher rates of GERD have been found in prior studies.  If they included children with fundoplication who were considered as having GERD (prior to fundoplication), then the GERD rate was 32%.

My take: This study showed that reflux in this cohort of children with EA was similar to the general population and likely indicates that a substantial portion of patients with EA do not need indefinite PPI therapy.  In children with more complex EA, PPI therapy is likely to be more beneficial.

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Recent (November 4th) GI-Related Tweets:

Diabetes Mellitus Associated with Acute Recurrent and Chronic Pancreatitis

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Briefly noted: MD Bellin et al. JPGN 2019; 69: 599-606.

Using the INSPPIRE database with 397 children with either acute recurrent pancreatitis or chronic pancreatitis, the authors examined the frequency of diabetes mellitus (DM).

Key findings:

  •  6% (n=24) had a diagnosis of DM. This is 30-fold higher than the general pediatric population
  • The group with DM was more likely to have elevated triglycerides (OR 5.21) coexisting autoimmune disease (OR 3.94) or pancreatic atrophy (OR 3.64)
  • The group with DM tended to be older with a mean at first diagnosis of acute pancreatitis of 12.9 years compared to 8.7 years in those who did not develop DM

Related blog posts:

 

Frontenac Hotel, Quebec City

Is CMV a Trigger for Necrotizing Enterocolitis?

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Previously, it has been recognized that increased rates of necrotizing enterocolitis (NEC) have been associated with viral outbreaks (eg. rotavirus, norovirus) (J Pediatr Surg. 2004;39:453–7 , 2010l;29: 644-7.).

A more recent study (S Panesso-Gomez et al. J Pediatr 2019; 214: 34-40) examines the association between cytomegalovirus (CMV) and NEC.

Key Findings:

  • In this retrospective cohort (2000-2016) with paraffin-embedded samples, the authors detected CMV by PCR or immunohistochemistry (IHC) in 7 (4%) of 178 infants with either NEC (n=143) or spontaneous intestinal perforation (n=35).
  • PCR was more sensitive and was positive in all 7 detected cases whereas IHC identified CMV in 4 of the cases.

One of the limitations of the study was the lack of a control group, though previous reports have found congenital CMV in 0.4% of preterm infants with very low birth weight (<1500 g) and in 0.5-1% of all liver births.

My take: This study shows an association between the presence of CMV and NEC; hence, CMV may be one of many factors which increase susceptibility to NEC.

Related blog posts:

 

 

Yonah Mountain

Esophageal Disorders: POEM in Kids, Mitomycin C for Refractory Strictures

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At our recent national meeting, Dr. Peter Kahrilas indicated that POEM (Per-oral Endoscopic Myotomy) was now the treatment of choice for most adults with achalasia (#NASPGAN19 Postgraduate Course -Part 3).

A Chone et al (JPGN 2019; 69: 523-7) provide recent multicenter retrospective data on POEM in the pediatric age group (mean age 14 years), n=117.

Key findings:

  • Clinical success, defined as Eckardt score ≤3 during followup, was achieved in 90.6% of cases. The Eckardt score was >3 in 5 (4.3%) and data was missing in 6 (5.1%)
  • Adverse events included 1 case with significant bleeding, 2 cases of aspiration pneumonia (related to anesthesia), 1 esopleural fistula (managed endoscopically), and 6 mild AEs (4 mucosomtomies, 2 subcutaneous emphysema)

Additional related blog posts:

D Ley et al (JPGN 2019; 69: 528-32) provide retrospective data on 39 patients, median age 19 months, with refractory esophageal strictures which were treated with mitomycin C.  The authors considered mitomycin C after a minimum of two previous dilatations.

Key findings:

  • Etiology: The majority had strictures/stenosis associated with esophageal atresia (n=25) followed by caustic ingestion in 9.
  • Number of stenosis: The majority (n=35) had a single stenosis.
  • In 26 patients (67%), topical application of mitomycin C was considered a success based on a reduction in the number of dilatations.  In this group, the number of dilatations dropped from 102 to 17 over a comparable period.
  • 16 (41%) never required further dilatation following mitomycin C application

My take: This study provides some of the best evidence that mitomycin C may be helpful.  Long-term followup and more studies are needed.

Related blog posts:

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.

Lincoln Park, Chicago

Why Fewer Children Have Immune-Tolerant Hepatitis B Infection Than Previously

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A recent study (KB Schwarz et al. JPGN 2019; 69: 588-94) highlights the chronic hepatitis B virus (HBV) phenotypes from a large pediatric North American cohort (n=371).

  • Immune-tolerant HBV was define by HBe-Ag-positivity along with normal ALT levels.
  • Inactive carrier were HBe-Ag-negative with low HBV DNA/normal ALT.
  • Chronic hepatitis B (HBeAg positive and HBeAg negative) had high HBV DNA and abnormal ALT values.
  • Indeterminant HBV had characteristics did not allow them to classified in these four categories.

Key findings:

  • If local laboratory normative values were used 36% of children would have been classified as immune-tolerant*.  However, this drops down to 12% if updated upper limits of normal (ULN) are used based on Figure 3.
  • Using updated ULN, 62% had immune active HBeAg+ disease, 12% with immune-tolerant HBV, 4% with immune-active HBeAg-negative disease, 6% with inactive carrier, and 16% indeterminant HBV.

*There are a few discrepancies between Figure 3 and the abstract data.  The abstract states that 82% would be considered to have chronic hepatitis B (this is 62% in figure 3). The abstract states that 35% were immune-tolerant based on local lab values.

The data presented were cross-sectional data at time of patient enrollment.

My take: this study shows that very few children in this cohort were immune tolerant based on more precise ULN values.  The authors note that the cohort who were immune tolerant were largely drawn from Asian children (most often infected perinatally).

Related blog posts:

Lincoln Park, Chicago

 

Surprising Genetic Mutations in Polyposis Study

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A recent cross-sectional study (PP Stanich et al. Clin Gastroenterol Hepatol 2019; 17: 2008-15, editorial 1942-44) identified a high frequency of genetic mutations among adults with at least 10 colonic polyps (cumulative burden of either adenomatous or hamartomatous).

This study had 3789 subjects who underwent multigene panel testing (MGPT) from 2012-16.

  • All subjects had at least 14 CRC-associated genes tested: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
  • A subset had 3 more newly recognized polyposis genes: GREM1, POLD1, and POLE

Key findings:

  • A mutation in at least 1 gene was found in 13.7%
  • In those with fewer than 20 cumulative adenomas, 7.6% had a disease-associated genetic mutation with the majority (5.3%) being nonpolyposis CRC genes
  • Younger patients, 18-29, were more likely to have mutations in any gene.  For example, among patients with 10-19 polyps, these younger patients had a mutation in one of these genes in 27.8%; this is more than double the rate in any other age group.
  • Hamartomatous polyps, regardless of number, had a very high yield with genetic testing: 40% with 10-19 polyps and 72% with 20-99 polyps.

Limitations:

  • There is a referral bias in that the population was derived from a testing laboratory (Ambry)
  • In clinical practice, genetic testing frequently results in variants of unknown significance

My take: This study shows that genetic mutations are fairly frequent in patients with cumulative polyp burden of 10 or more, especially in younger age groups.  The surprising finding is the high frequency of nonpolyposis CRC genes.  Thus, in patients with adenomatous polyposis, testing beyond APC and MUTYH may be needed.

Related blog posts:

Atlanta Botanical Garden

Discrimination, Abuse, and Harassment in Medical Training

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A recent study (Y-Y Hu et al. NEJM 2019; 381: 1741-52) reported high rates of discrimination, abuse, and harassment based on a cross-sectional survey of general surgical residents (n=7409) in 2018.

Key findings:

  • 31.9% reported gender discrimination and 16.6% reported racial discrimination–with main source being patients/families
  • 30.3% reported verbal or physical abuse and 10.3% reported sexual harassment -with attending surgeons being the most frequent sources
  • Residents who experienced discrimination, abuse or harassment were more likely to have symptoms of burnout (OR 2.94) and suicidal thoughts (OR 3.07).  Overall, weekly burnout symptoms were noted in 38.5% of residents and 4.5% reported suicidal thoughts in previous year

The authors note that there were substantial numbers of programs with very low rates of mistreatment which indicates that improvement in training environment is feasible.

My take: This is a black eye for the entire healthcare field.  It is important to address these pervasive problems and to determine the rate of these issues in other areas of medicine.

Botanical Gardens, Chicago

Using Less Steroids for Autoimmune Hepatitis

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A recent retrospective study (S Pape et al. Clin Gastroenterol Hepatol 2019; 17: 2068-75) with 451 adults (1978-2017) examined outcomes among patients based on steroid dosing.

A high-dose group (n=281) with initial prednisone/prednisolone dose of ≥0.5 mg/kg/day was compared with a low dose group (n=170) <0.5 mg/kg/day.  The low dose group had higher rates of cirrhosis (25.9% vs. 15.3%) but lower median ALT values (7.1 ULN vs. 13.4 ULN) and lower median bilirubin values (48 vs 29 micromol/L).

Key findings:

  • There was no difference in rates of transaminase normalization at 1 year: 76.2% vs 77.6%
  • Transaminase normalization was lower in patients with cirrhosis 58.1% compared to 70.7% with cirrhosis
  • Most patients were receiving low-dose steroids at 6 months, 87.4% in high-dose group compared to 83.5% in low-dose group
  • Cumulative steroid dose was lower in low-dose group, with median of 2573 mg over 6 months compared to 3780 mg

Though, not studied in this report, AASLD has recommended use of immunoglobulin levels may help with immunosuppression titration. The editorial (pg 1948-49) notes that budesonide is another alternative for AIH without cirrhosis, though “long-term outcomes including histologic remission and appropriate tapering strategy for budesonide are currently lacking.”

My take: Particularly in patients without severe inflammation, lower steroid doses can be considered for autoimmune hepatitis.

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Atlanta Botanical Garden

China Is Catching and Passing U.S. with NAFLD Plus Updates

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F Zhou et al. Hepatology 2019; 70: 1119-33. The authors performed a systematic review (n=392 studies, more than 2 million subjects) and found that NAFLD in China increased from 25.4% in 2008-2010 to 32.3% in 2015-2018. The pooled prevalence across all studies was 29.2%. The associated editorial speculates that some of this increase is related to diet changes as well as PNPLA3 gene.  This allele “is more common among East Asians than Caucasians”  It is lower in African Americans in the U.S. which helps explain why this population is at reduced risk.

JB Schwimmer, JS Johnson et al Gastroenterol 2019; 157: 1109-22.  In this prospective study with 87 children (89% Hispanic), the authors associated fecal microbiomes with NAFLD and NASH.  Both NAFLD and NASH were associated with intestinal dysbiosis with lower diversity and high abundance of Prevotella copri. Full text link: Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease

S Pelusi et al. Clin Gastroenterol Hepatol 2019; 17: 2310-9.  This study analyzed data from 1738 subjects (45% with severe obesity) who had undergone liver biopsy.  132 of 389 (33.9%) with significant fibrosis did NOT have nonalcoholic steatohepatitis (NASH) and 39 patients (10%) had no inflammation. NASH diagnosis required steatosis (≥5% of hepatocytes), hepatocellular ballooning, and lobular inflammation. Factors associated with significant fibrosis in the absence of NASH, included fasting hyperglycemia, severe steatosis, mild inflammation or ballooning, and PNPLA3 1148M variant.  My take: this study shows that the finding of NASH on liver biopsy is NOT required for the development of severe liver disease related to NAFLD.

D Linden et al. Molecular Metabolism 2019; 22: 49-61. This study, summarized in Gastroenterol 2019; 157: 1156-9) showed that PNPLA3 silencing with antisense oligonucleotides ameliorates NASH in PNPLA3 1148M knock-in mice.  The summary notes that the mutated 1148 M PNPLA3 protein variant accumulates on lipid droplets altering clearance and affecting triglycerides and phospholipid turnover.