Rectal Suction Biopsies Less Accurate in Infants <40 days

Briefly noted:

RJ Meinds et al Clin Gastroenterol Hepatol 2015; 13: 1801-07. In this retrospective analysis (1975-2011) of 529 rectal suction biopsies (RSBs) from 441 patients, the authors note lower sensitivity for RSB in infants <40 days.

From Table 3:

  • Hirschsprung’s disease patients <40 days: true-positive RSB 56/111 (50%), inconclusive RSB 32/111 (29%) and false negative 23/111 (21%)
  • Hirschsprung’s disease patients >40 days: true-positive RSB 136/154 (88%), inconclusive RSB 14/154 (9%) and false negative 4/154 (3%)
  • Non-HD patients <40 days: inconclusive RSB 2/48 (4%), false-positive RSB 0/48 (0%)
  • Non-HD patients >40 days: inconclusive RSB 10/216 (5%), false-positive RSB 1/216 (<1%)

Bottomline: This study may need to be replicated due to improvements in biopsy analysis (eg. calretinin); however, in the first 40 days of life, RSBs are more often inconclusive and/or false-negatives.  The use of anorectal manometry may be helpful.

Related blog posts:

Coors Field

Work on Both Ends

Two articles provide some insight into endoscopic interventions on both ends of the gastrointestinal tract.

In the first article (JPGN 2014; 59: 608-11), the authors retrospectively studied 11 children who received mitomycin-C concurrently with endoscopic dilatation for the treatment of anastomotic strictures after esophageal atresia repair.  Key finding: 8 of 11 achieved resolution of their strictures, 2 remained with stenosis, and 1 needed surgical correction. However, the authors found no benefit of mitomycin C in the resolution of the strictures compared with endoscopic dilatation alone in historical controls (n=10). In fact, in this small study, the control group patients had fewer endoscopic dilatations (3.7 vs. 5.4 dilatations per patient) and 9 of 10 achieved stricture resolution.

In the second article (JPGN 2014; 59: 604-08), the authors retrospectively reviewed the outcome of children (n=33) with surgically-treated Hirschsprung’s disease (HD) who were treated with intrasphincteric Botox injections for obstructive symptoms. In these children with median age of first Botox injection was 3.6 years; a median of 2 injections were given.  26 (79%) had had a transanal endorectal pull-through.  Key finding: initial improvement was noted in 76% and “good/excellent” long-term response was evident in 52% (Table 2).

Bottomline: Botox therapy appears helpful for non-relaxing sphincters in HD whereas mitomycin-C remains an unproven therapy for esophageal strictures.

Also briefly noted: JPGN 2014; 59: 674-78.  “Use of cyproheptadine in young children with feeding difficulties and poor growth in a pediatric feeding program.” n=127.  Of the 82 who took cyproheptadine regularly, 96% reported a positive change in feeding behaviors and there was a significant improvement in weight gain.

Also, with regard to stooling problems, Sana Syed (Emory GI fellow) pointed out a useful website that emphasizes proper positioning for functional constipation:  While the website promotes their product to provide proper foot support (with elevation), there are other ways to get a similar result.  As noted previously (“Poo in You” Video | gutsandgrowth) proper positioning can help a lot.

Related posts:


“Genetic Testing and the Future of Pediatric Gastroenterology”

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 ( 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
  • 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:




Reducing Diagnostic Uncertainty in Hirschsprung’s Disease

Previously this blog noted the emergence of calretinin immunohistochemisty (What is calretinin? | gutsandgrowth).  Now, more data has been published indicating that calretinin reduces inconclusive rectal biopsies for the diagnosis of Hirschsprung’s disease (JPGN 2014; 58: 603-07).

The authors analyzed data retrospectively for 45 patients prior to the use of calretinin and 42 patients after calretinin introduction.

Key finding: 37.8% (17 of 45) of patients had inconclusive rectal biopsies prior to use of calretinin compared with 11.9% (5 of 42) after including calretinin immunohistochemistry.

Primary Enteric Nervous System Disorders

If you are wondering what these are, you may want to review a recent consensus statement (JPGN 2013; 57: 677-86).

This ‘practical guide’ discusses Hirschsprung’s disease, intestinal neuronal dysplasia, chronic intestinal pseudo-obstruction, ultrashort segment Hirschsprung’s disease, hypoganglionosis, and ganglioneuromatosis in MEN 2B.

Most of the focus is on Hirschsprung’s disease including the intricacies of diagnosis, clinical presentation, and genetics.  While the authors do mention the PHOX2B gene and others, there is not a discussion of Ondine’s curse (Congenital central hypoventilation syndrome and Hirschsprung’s ).  One point that I think is important (but not discussed in the above reference) in patients who have Ondine’s curse and Hirschsprung’s is determining whether a family member may have a milder phenotype that could still place them at risk for sudden death (eg. after a simple sedation procedure).

Related blog post:

What is calretinin? | gutsandgrowth