“Bowel Sounds” Pediatric GI Podcast: Dr. Martin and Dr. Vartabedian

It’s been nearly two years since the start of the NASPGHAN Bowel Sounds Podcast.

They are really good. While I am more of a visual learner, I like listening to the hosts banter at the beginning and then their capable interviews. The Podcasts have chosen terrific guests. You can read about and listen to all of the episodes at the NASPGAN website (link below), or listen on the go on Apple Podcasts, Spotify, Google Podcasts, or wherever else you listen to podcasts.

Here’s the NASPGHAN link: Bowel Sounds: The Pediatric GI Podcast

The two most recent podcasts (Dr. Martin and Dr. Vartabedian) exemplify the wide range of information available.

Dr. Martin Martin reviews the topic of congenital diarrheas and enteropathies (CODEs). Some key points:

  • History: Timing and Severity. Onset in the first week of life is suggestive of a congenital diarrhea (CODE). In those with later onset (eg. >4 weeks), need to consider infections, post-infectious diarrhea, and allergic disorders
  • Workup if suspicious of CODE -detailed in UpToDate (Dr. Martin is one of the authors). Many kids need serum studies, stool studies, imaging (AXR, UGI/SBFT) and EGD/Flex sig. In UpToDate, search either “congenital diarrhea” or “approach to chronic diarrhea in neonates and young infants (<6 months)” (36 pages)
  • Treatment: Most kids need a short (~24 hr) trial of NPO when there is adequate IV access to determine if diarrhea is malabsorption (goes away with fasting) and if diarrhea persists which is suggestive of an electrolyte transport-related diarrhea (aka. secretory diarrhea)
  • Dr. Martin advises use of bolus feeds when feeding trials are introduced in this population to get to an answer quicker. Usually with significant diarrhea, it is reasonable to start with a carbohydrate-free formula (eg. RCF formula). If there is not diarrhea with RCF, this suggests a carbohydrate malabsorption whereas ongoing diarrhea is suggestive of a more generalized malabsorption
  • Genetic testing should be performed earlier in the evaluation of those with a high suspicion of a CODE (eg. 1st week of life onset, severity, polyhydramnios, consanguinity) if the infectious workup is negative

Links:

  1. Advances in Evaluation of Chronic Diarrhea in Infants (nih.gov)
  2. PediCODE
  3. www.uptodate.com – Title: Approach to chronic diarrhea in neonates and young infants (<6 months)
  4. https://www.preventiongenetics.com/

Related blog posts:

Dr. Vartabedian, in his episode, discusses the importance of “owning your online identity as a physician, something “Dr. V” has written and spoken about extensively, including on his blog at 33charts.com” (from NASPGHAN website). He explains that everyone has a presence online and physicians can influence the content. At the very least, most physicians should make sure that their institutional profile looks good and that they take advantage of placing a profile on LinkedIn.

Other key points:

  • Dr. V’s book is available on 33charts (see link below)
  • Physicians can do a “vanity” search on Google and see what is posted about them
  • Dr. V recommends a book called “Keep Going” by Austin Kleon. “Whether you’re burned out, starting out, starting over, or wildly successful, Keep Going will help you stay on the path to more creative work.” (from Austin Kleon website)
  • Dr. V discusses a range issues which include negative physician reviews, online Trolls, and patient privacy

Links:

  1. The Public Physician | A Guide to Life in a Connected World
  2. 33charts.com (also be sure to sign up for the 33mail newsletter while you are there)

Related blog posts:

DGAT1 Deficiency

Briefly noted: JM van Rijn et al. Gastroenterol 2018; 155: 130-43.  This study of 10 patients from 6 families (5 had consanguinity) was the largest cohort to date describing the clinical features in this disorder and used patient-derived fibroblasts and organoids to understand the pathophysiology.

Key clinical features:

  • Early-onset vomiting and/or diarrhea
  • Protein-losing enteropathy/hypoalbuminemia

Key finding in study:

  • These patients had altered lipid metabolism and were susceptible to lipid induced cell death.  Thus DGAT1 mutations cause congenital diarrhea and this is linked to fat intolerance.

Related blog posts:

Sunshine Meadows, Banff Natl Park

Lessons in Diarrhea (part 2)

More from the following: JR Thiagarajah et al. Gastroenterology 2018; 154: 2045-59. (Senior authors/corresponding authors: Yaron Avitzur and Martin Martin).  This article provides an excellent review of persistent infantile diarrhea and provides algorithms to help in the evaluation of these disorders.  These algorithms incorporate the role of exome sequencing.

The authors divide infants with watery diarrhea/CODEs into five categories -detailed in their Table 2 which also has OMIM #, inheritance pattern, gene name, protein function:

#1 Epithelial nutrient/electrolyte transport:

  • congenital chloride
  • congenital sodium
  • glucose-galactose malabsorption (GGM)
  • primary bile acid diarrhea
  • acrodermatitis enteropathica

#2 Epithelial enzymes and metabolism

  • Congenital lactase deficiency
  • Sucrase-isomaltase deficiency
  • Trehalase deficiency
  • Enterokinase deficiency
  • DGAT1 deficiency
  • PLVAP deficiency
  • Abetalipoproteinemia
  • Hypobetalipoproteinemia
  • Chylomicron retention disease
  • Dyskeratosis congenita
  • Kabuki syndrome

#3 Epithelial trafficking and polarity

  • Microvillus inclusion disease
  • Tufting enteropathy
  • Syndromic Na diarrhea
  • Trichohepatoenteric syndrome 1 & 2
  • Familial hemophagocytic lymphohistiocytosis 5
  • TTC7A deficiency

#4 Enteroendocrine cell dysfunction

  • Enteric anendocrinosis
  • X-linked lissencephaly and MR
  • Proproteint convertase 1/3 deficiency
  • Mitchell-Riley syndrome

#5 Immune dysregulation-associated enteropathy (partial list)

  • IPEX
  • ICOS deficiency
  • ADAM17 deficiency
  • EGFR deficiency
  • CD55 deficiency
  • CTLA4 deficiency
  • LRBA deficiency
  • XIAP

So, to tackle this long list the authors recommend combining typical clinical evaluation along with early genetic evaluation.

Clinical evaluation of watery diarrhea:

  • Early endoscopic biopsy (EGD/Flex sig) -obtain samples for routine histology and for electron microscopy.  Disaccharidase evaluation can be helpful; though, “these enzymatic assays are often unreliable due to poor sampling or in the setting of inflammation or villus atrophy due to secondary disaccharidase deficiency.”
  • If normal villus/crypt architecture, the next step is determining whether the diarrhea improves with fasting. This could indicate GGM, sucrase-isomaltase, congenital lactase deficiency or enteroendocrine cell loss.  The first three can be elucidated by offering specific dietary challenges using either a feeding trial with carbohydrate-free or fructose-based formula.
  • If normal villus/crypt architecture, and if the diarrhea does not improve with dietary manipulation, consider congenital chloride diarrhea, congenital sodium diarrhea, primary bile acid mediated diarrhea, and hormone-induced diarrhea.
  • If normal villus/crypt architecture, and there is hypoalbuminemia/PLE, consider DGAT1 deficiency, CD55 deficiency, and lymphangiectasia.
  • If abnormal villus/crypt architecture, then this is likely either a postinfectious/autoimmune disorder or due to an epithelial structural defect like tufting enteropathy, microvillus inclusion disease, TTC7A deficiency or SKIV2L defect

When one looks at the magnitude of disorders that could result in CODEs and their potential clinical importance, it is not surprising that the authors state emphatically:

“In cases of a suspected CODE, where the diagnosis based on clinical evaluation is unclear, it is now standard of care to perform whole-exome sequencing to identify a possible causative genetic mutation.”

My take: This article provides a great deal of information in tackling a difficult problem.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Little Talbot State Park (near Amelia Island)

Lessons in Diarrhea (part 1)

One of the most influential medical articles that I’ve read this year: JR Thiagarajah et al. Gastroenterology 2018; 154: 2045-59. (Senior authors/corresponding authors: Yaron Avitzur and Martin Martin).  This article provides an excellent review of the terminology and provides algorithms to help in the evaluation of chronic diarrhea in infants.  These algorithms incorporate the role of exome sequencing.

The first part of this review focuses on terminology:

  • For those with persistent and severe diarrhea that is not due to an acquired short bowel syndrome (eg. from necrotizing enterocolitis, gastroschisis, or volvulus), the authors use the term congenital diarrhea and enteropathies (CODEs).  They suggest using CODEs in place of intractable or protracted diarrhea of infancy.
  • Instead of osmotic diarrhea, the authors prefer diet-induced diarrhea since all diarrhea involves osmotic forces.  Typically, with this type of diarrhea, stool osmotic gap is >100 mOsm.
  • Secretory diarrhea “is also imprecise…We prefer to use the term electrolyte-transport-related diarrhea” (eg. congenital sodium or congenital chloride diarrhea)

Key points:

  • Most acquired diarrhea is related to infectious agents and to allergic disorders. Though, persistent diarrhea after an infection could be an early sign of a primary immunodeficiency.
  • Stool osmotic gap: = 290 – 2 x (Stool Na + Stool K).  Osmotic gap >100 mOsm is high, <50 mOsm is low.
  • Stool osmolality in almost all cases is isomolar to serum (~290).  If there is suspicion of improper collection or tampering, then this can provide objective evidence of this.
  • Reducing substances >0.5% indicates malabsorption of monosaccharides. Low pH (<5.3) is indicative of carbohydrate malabsorption (due to abundance of short-chain fatty acids that are products of fermentation)
  • Elastase is “unchanged by intestinal proteases and if low can imply pancreatic insufficiency.”  Falsely-low values can occur due to dilution in high-volume diarrhea.
  • Alpha-one-antitrypsin is largely resistant to intestinal proteases and elevation indicates excess enteric protein loss (eg. protein-losing enteropathy)

Diagnostic evaluation:

  • See figure 1 in review.  Initial evaluation after exclusion of acquired diarrheas (eg infection/allergic): History, Blood tests (CBC, CMP, CRP, ESR, IgG, lipid panel), Stool tests (electrolytes, reducing substances, elastase, fecal fat, A1AT, pH, calprotectin/lactoferrin).
  • Determining stool output may require a “urine catheter for a few days” for accuracy and help elucidate the effect of fasting on stool output.
  • Figure 2 divides evaluation based on type of diarrhea: watery, fatty, and bloody.
  • Fatty diarrhea may be due to pancreatic insufficiency, abetalipoproteinemia and chylomicron retention disease.  The latter two disorders typically are indicated by fat-laden enterocytes in histologic sections
  • Bloody diarrhea “should precipitate investigation for very-early-onset inflammatory bowel disease, autoimmune enteropathy, or primary immunodeficiency”
  • Watery diarrhea –see tomorrow’s post.  Before undergoing extensive evaluation, the authors recommend obtaining an UGI/SBFT to exclude congenital short bowel syndrome.

My take: after initial exclusion of common causes for diarrhea in infancy, early endoscopy is needed along with early use of genetic testing.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Little Talbot State Park

 

World Congress 2016 Postgraduate Course

I’ve attached (with permission) the syllabus from the World Congress 2016 Postgraduate Course: 2016-world-congress-postgraduate-course-syllabus

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One lecture that I will highlight with a few slides is from Dr. Martin Martin (pg 53-62) which emphasizes a new model for evaluating neonatal intestinal failure/congenital diarrhea by using whole exome sequencing –see slides below.

Other pointers:

  • Pg 82.  Breastmilk associated with shorter duration of TPN dependence in short bowel syndrome
  • Pg 137. Look for vasculopathy (MRI/MRA) and renal disease in Alagille syndrome
  • Pg 152. Lactated ringer’s likely better in acute pancreatitis than normal saline.
  • Pg 171. If constipation at less than 1 year is untreated, >60% have issues with constipation at age 3.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

If I ever see an infant with Congenital Sodium Diarrhea

If I ever see an infant with Congenital Sodium Diarrhea (CSD), I will revisit: AR Janecke et al JPGN 2016; 63: 170-6.

A couple of pointers from this article:

  • CSD represents a group of clinical conditions with high fecal sodium losses at birth  Three mutations: SPINT2, GUCY2C, and SLC9A3 account for the majority of cases.
  • IBD occurs in some of these children.
  • GUCY2C causes a secondary loss of sodium-proton antiporter 3 function related to mutations in the receptor for guanylate cyclase C (GC-C).  (I find this particularly interesting due to work in my fellowship with guanylin which binds to GC-C.)
  • SPINT2 is associated with a syndromic CSD which may include choanal/intestinal atresias, cleft palate, hypertelorism, and polydactaly.  Unlike classical CSD (due to SLC9A3), this form of CSD is characterized by associated villous atropy and some characteristic tufts.
  • Table 1 lists other causes on the differential diagnosis including microvillus inclusion disease and epthelial dysplasia (tufting enteropathy)

Related blog posts:

Mountain Goat at Glacier Natl Park. Antenna part of a study.

Mountain Goat at Glacier Natl Park. Antenna part of a study.

Another Rare Cause of Neonatal Diarrhea

A well-described case report (B Harter et al. JPGN 2016; 62: 577-80) provides a description of proprotein convertase 1/3 (PC1/3) deficiency. To date, only 21 cases have been reported.

Clinical features: congenital diarrhea and polyuria; normal endoscopy/histology. This patient required parenteral nutrition until 11 months of age. Her polyuria resolved at 13 months of age. Low serum levels of c-peptide and insulin along with elevated pro-insulin, combined with the polyuria, were suspicious for PC1/3 deficiency. This patient’s diagnosis was established with genetic analysis of the PCSK1 gene.

PC1/3 is responsible for peptide hormone processing in endocrine cells in the gut, and has targets in the hypothalamus and pancreas. Growth hormone deficiency, adrenal insufficiency, diabetes insipidus, and hypogonadism are commonly observed.

Related blog posts:

Gibbs Gardens

Gibbs Gardens