Category Archives: Pediatric Gastroenterology Intestinal Disorder

Something new for blue (BRBNS)

Posted on by

A case report describes the use of low-dose sirolimus (rapamycin) for treating blue rubber bleb nevus syndrome (BRBNS).  (Pediatrics 2012; 129: e1080-84). This patient, an 8-year-old girl from Turkey) presented with massive gastrointestinal bleeding had multiple venous malformations all over her body, especially throughout her gastrointestinal tract.

Before instituting sirolimus, patient had failed several agents: prednisolone, interferon-α, propranolol, and aminocaproic acid.  Sirolimus was dosed at 0.05-0.1 mg/kg as an antiangiogenic agent with a goal of maintaining a trough level between 1 and 5 ng/mL.  The lesions decreased in size but did not disappear.  Initially, patient received therapy with propranolol concomitantly.  Dramatic improvements in hemoglobin were noted after starting sirolimus therapy.

Additional references:

  • -Pediatr Blood Cancer 2011; 57: 1018-24.  Use of sirolimus for complicated vascular anomalies in children
  • -Pediatrics 2001; 107: 418.  Case report of BRBNS
  • -JPGN 2001; 33:183-188. Use of octreotide in BRBNS

Diarrhea, GC-C and guanylin

Posted on by

During my fellowship, I participated in research studying the effects of guanylin and its interaction with the receptor, guanylate cyclase C (GC-C).  So whenever clinical articles demonstrate clinical significance, I am interested.  This month there is evidence that some cases of familial diarrhea are due to mutations which activate the GC-C receptor (NEJM 2012; 366: 1586-95).

The authors describe a novel dominant disease in 32 members of a Norwegian family due  to a mutation in the sequence of GUCYC which encodes GC-C.  Exposure of this mutant receptor to its ligands results in increased cyclic guanosine monophosphate (cGMP).  This in turn likely causes hyperactivation of the cystic fibrosis transmembrance regulator (CFTR)  resulting in diarrhea.  Individuals with this mutation tended to have mild chronic diarrhea with an early onset as well as a susceptibility to inflammatory bowel disease and small bowel obstruction.

While this mutation is rare, there is a larger role for GC-C.  Heat-stable enterotoxins form E. coli bind to this receptor starting a cascade which results in diarrhea.  Since there had to be a role for GC-C other than facilitating development of diarrhea after exposure to pathogens (Why would our body create a receptor for a pathogen?), researchers discovered an endogenous ligand for GC-C, guanylin.   Guanylin acts as an agonist of  GC-C and regulates electrolyte and water transport in intestinal and renal epithelia.  In addition, guanylin and GC-C serve as a model for intestinal gene regulation.  Also, GC-C has been investigated as a predictive marker for colorectal cancer and for a role in renal electrolyte transport in humans; in animals, GC-C and its ligands have been shown to have effects on behavior and satiety.  

Additional references:

  • -Steinbrecher KA, Cohen MB. Transmembrane guanylate cylase in intestinal pathophysiology. Curr Opin Gastroenterol 2011; 27: 139-45.
  • -Gastroenterology 2010; 138: 886.  Linaclotide -a guanylin analog –use for constipation.
  • -Hochman JA, Sciaky D, Whittaker T, Hawkins JA, Witte DP, Cohen MB. “HNF-1 Regulates the Transcriptional Activation of Guanylin” Am. J.  Physiol. 273 (Gastrointest. Liver Physiol. 36): G833-G841, 1997.
  • It’s often elemental  Previous post discusses protracted diarrhea of infancy

Improve Care Now

Posted on by

Several years ago, “ImproveCareNow” Network was established with a goal of improving the quality of care children with inflammatory bowel disease. https://improvecarenow.org/ (http://www.youtube.com/watch?v=beG2eMROWqg)

Documentation of some outcomes of this effort have now been published (Pediatrics 2012; 129: e1030-e1041).  In this study from six U.S. centers, data from 843 children with Crohn’s disease and Ulcerative Colitis were available.  Centers were eligible to participate if they did not have extensive quality improvement (QI) experience and if they were able to enroll >75% of their IBD patients.  During the course of the study (2007-2010), there were increases in the proportion of patients with measurement of thiopurine methyltransferase (TPMT) before initiation of thiopurines, increased percentage of individuals receiving an appropriate thiopurine dosage, and an increased percentage of patients with inactive disease.  In Crohn’s disease, the number with inactive disease changed from 55% to 68%; in ulcerative colitis, the number increased from 61% to 72%.  

This study shows significant progress in these patients and the potential benefit of a more-structured approach.  However, some of the improvements in these outcomes may not be to process improvements. 

Study limitations:

  • The study does not document the rate of inactive disease in non-participating centers; thus there is not an adequate control population.  Given more widespread use of biologic therapies, this may account for much of the improvement in outcomes.   In fact, the study does not describe the percentage of patients receiving thiopurines or biologic agents.
  • The use of the physician global assessment (PGA) as indicative of disease activity.  The authors acknowledge that “PGA ….is a relatively subjective measure.”  A more reliable measure of disease activity like a stool calprotectin, endoscopy, or imaging study improvement would have been helpful.  
  • Better documentation or better outcomes? It is not clear whether some of the improvement reflects better documentation or improved care delivery.

Despite the limitations of this study, it is a good starting point.  The goal of improving the care of patients is shared by almost all physicians.  One way to start making a difference is measuring specific outcomes and targeting specific goals/checklists. Going forward with QI there are many QI hurdles: 

  • Defining optimal care is nearly impossible, there are few trials comparing efficacy & difficult to judge risk/benefit ratio of many therapies.
  • Difficulty selecting appropriate outcome measures -indications for hospitalization and surgery are not clear-cut in many cases.  Surgery may be an appropriate treatment rather than a negative outcome. 
  • Risk adjustment is an imperfect science.

Goals with Quality Improvement:

  • Plan-Do-Study-Act cycles.
  • Learning from high-performing centers -benchmarking

Warranted vs unwarranted variations:
Unwarranted: selecting inadequate dosing of medications, failure to check for TB before remicade/biologics, failure to consider drug interactions, failure to discuss options with families
Warranted: variation due to differences in disease (eg budesonide for ileitis but not pancolitis), variation driven by patient preferences (eg. using NG instead of corticosteroids)

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

“Not everything that counts can be counted, and not everything that can be counted counts.” –Albert Einstein

Additional references on quality improvement:

  • Free Self Management Handbook endorsed by ImproveCareNow:

https://improvecarenow.org/patients/self-management-handbook

  • -JPGN 2009; 49: 272.  Review of quality measures/history.
  • -Kohn LT, et al. To Err is Human: Building Safer Health System.  Nat’l Academy Press; 2000
  • -Crossing the quality chasm.  Wash DC: Nat’l Academy Press; 2001.
  • -Clin Gastro & Hep 2010; 8: 709.  Quality indicator sets in cirrhosis.
  • -J Pediatr 2005; 146: 744-50.  Bucuvalas JC et al.  Adjusting calcinerin inhibitor dosing
  • -IBD guidelines: www.cincinnatichildrens.org/svc/alpha/health-policy/ev-based/ibd.htm
  • -JPGN 2009; 49: 297.  Variation in care in pediatric Crohn disease. (Our center participated in this study)
  • -J Pediatr 2009; 154: 582.  Ventilator assoc pneumonia reduced w bundle of hand hygiene, elevated HOB, not changing ventilator circuits except when soiled & mouth care
  • -“The Learning Curve”(Atul Gawande) in The Best American Essays 2003 -some CF ctrs outperform, extending life expectancy ~14yrs.
  • -” A Surgeons Notes on Performance-Atul Gawande
    -NEJM 2007; 357: 2652.  Nice editorial.
  • www.icsi.org
  • www.qualityforum.org
  • www.ambulatoryqualityalliance.org
  • www.ncqa.org
  • www.cms.hhs.gov/hospitalqualityinit

Comments from lead author forwarded to blog:

Thanks for including our recent paper in your blog.  I agree with the study limitations as you mentioned, but wanted to put a couple of things in context.  We actually thought very hard about the issue of a control group, and specifically how to determine what the remission rate would be without the intervention.  We could not come up with a reasonable comparator (very few people/groups outside of ICN even know what the remission rate of their population is).  One very rough measure (which we did not feel was legitimate to include) is the rate of remission for new sites as they are joining the collaborative.  Established sites with complete participation have better outcomes than newer sites or sites that participate less fully, suggesting that at least a significant portion of the effect is due to the QI intervention rather than secular trend.  As far as the objective measures for outcomes, I know you realize that we are not able to mandate specific objective evaluations for a QI/observational research study, so we may never be able to use mucosal healing (for example) as our measure of remission.  However you probably noticed in the paper that we did demonstrate improvements in objective measures including sPCDAI, PUCAI and use of corticosteroids.  Certainly improvements in process measures may have been due in part to better documentation, but it is unlikely that objective outcome measures improved due to documentation. Thanks again for sharing our work with your audience.

Pierre Robin and what else?

Posted on by

In a large pediatric center, patients with Pierre Robin Sequence (PRS) are routinely seen by genetics and for good reason.  Underlying syndromic features were present in 60% of a recent retrospective review (J Pediatr 2012; 160: 645-50).

Most common syndromes with PRS include the following:

  • Stickler syndrome (22% pf all cases)
  • 22q11.2 deletion syndrome/velocardiofacial syndrome
  • Marshall syndrome
  • Moebious syndrome
  • Cornelia de Lange syndrome
  • Treacher Collins syndrome
  • Fetal alcohol syndrome
  • Van der Woude syndrome
  • Oculo-auricular-vertebral spectrum

For gastroenterologists, the article notes that 43% of the San Diego cohort required tube feeding whereas 79% of the Cleveland cohort needed tube feedings.  Overall, average was 52% needing tube feeds.

Additional references:

  • -J Pediatr 2011; 159: 887.  Feeding problems common in UAO/Robin-like phenotype.
  • -Burstein FD, Williams JK.  Mandibular distraction. Plast Reconstr Surg 2005; 115: 61-7.
  • www.vcfsef.org
  • www.sticklers.org
  • -J Pediatr 2002; 140: 719.  Frequent upper esophageal/oral motor dysfxn (24/28)
  • -J Pediatr 2001; 139: 588. n=117.  descriptive study.  35% c syndrome, 48% isolated, 17% c associated anomalies.
  • -JPGN 2001; 32: 297.  Frequent oroesophageal motor disorders in these patients.  86% required prolonged NG feeds.

Recurrent pancreatitis and genetic underpinnings

Posted on by

While the absolute number of patients with genetic causes of pancreatitis is small, due to frequent hospitalizations, this remains a significant problem.  This month additional information on genetic predisposition for pancreatitis is available (JPGN 2012; 54: 645-50).

Sultan et al (Milwaukee, WI) reviewed the charts of children <18 years with recurrent acute pancreatitis (RAP) and patients with chronic pancreatitis (CP) from 2000-2009.   RAP was considered if patient had a minimum of two distinct episodes of acute pancreatitis.  Acute pancreatitis was considered the diagnosis if patient had typical symptoms associated with 3-fold elevation of amylase or lipase or imaging changes consistent with acute pancreatitis. CP was defined as a minimum of 2 episodes of acute pancreatitis associated with pancreatic duct abnormalities or pancreatic insufficiency.

Among this cohort of 29 children, 23 (79%) had mutations which have been associated with genetic pancreatitis (GP).  Family history was positive in only five patients.

  • CFTR mutation in 14 (48%): two had homozygous mutations, six heterozygous, and four had 5 T variants.  The importance of a single CFTR mutation in contributing towards pancreatitis is unclear.  However, the Wisconsin population has a carrier frequency of 1:32; the striking difference in frequency  indicates that even a single mutation may be important in the pathogenesis of RAP.
  • SPINK1 (serine protease inhibitor Kazal type 1) in 8 (27%).  SPINK1 mutations occur in 1-3% of the general population.  It is often a modifying factor rather than an isolated causal factor in the development of RAP.  Four of the patients with SPINK1 mutations also had a CFTR mutation.
  • PRSS1 (cationic trypsinogen gene) in 7 (24%).  Individuals with these mutations are considered to have hereditary pancreatitis, an autosomal disease with incomplete penetrance.
  • Only one patient was tested for chymotrypsin C gene (CTRC) –tested negative.

Seven patients with RAP did not undergo genetic testing & were excluded from the study.  These patients had other known causes of RAP: 3 had gallstones, 2 had pancreas divisum, 1 had a metabolic disorder, and 1 had a medication-induced pancreatitis.  The authors note, however, that patients with pancreas divisum have had genetic mutations identified in other studies.

Additional References:

  • www.uni-leipzig.de/pancreasmutation. This link will take you to the hereditary pancreatitis database where you can search for the specific mutation you identified and find articles dealing with a variety of aspects of that particular mutation.
  • 2011 Naspghan Postgraduate Course:
    Pancreatitis Workup
    -1st bout, check U/S, trig
    -if 2nd bout, suggested to check MRI, genetics (SPINK1, PRSS1, CFTR), sweat test, fecal elastase, possibly IgG4/ANA
  • OMIM#167800/276000
  • -Gastroenterology 2006; 131: 1844.  Mouse model w R122H Trypsiongen expression.
  • -Whitcomb DC. Gut 2004; 53: 1710-17. test for PRSS1 (cationic trypsinogen), SPINK1 (Serine protease inhibitor, Kazal Type 1), and CFTR gene.
  • -JPGN 2002; 34: 1A pg 444. n=108 with hereditary or idiopathic pancreatitis. (28% had + fhx)  12 c PRSS1 mutation, 24 c SPINK1 (21 s fhx); 22 had + CFTR mutation.
    -Pancreatology 2001; 1: 405-415.  Consensus guidelines for testing for H. Pancreatitis. PRSS1 gene -cationic trypsinogen
    http://www.pancreas.org/assets/pdfs/Pancreatology/HPgeneTestConsensus.pdf
  •  David Whitcomb’s laboratory at the University of Pittsburgh. The test is commercially available there. Their web site for the forms is:
    http://www.pitt.edu/~whitcomb/HPINFO/MolGenTest.html
  • -JPGN 2011; 52: 262. Review.
  • -J Pediatrics 2011; 158: 612.  Acute pancreatitis can result in diabetes.
  • -Clin Gastro & Hep 2010; 8: 410-416, 417. REVIEW of acute pancreatitis.  Rec NJ generally over TPN.
  • -Clin Gastro Hep 2010; 8: xxii.  Anomalous pancreatobiliary jxn as a cause.
  • -JPGN 2009; 49: 137.  Pancreatitis assoc w celiac
  • -Clin Gastro & Hep 2009; 7: 702.  Harmless Acute pancreatitis score.  Nonsevere when NL hgb, NL creatitine, and no rebound tenderness/guarding
  • -Alim Pharm Ther 2008; 28: 777-781.  Use of a low fat diet helped shorten hospital stay among adult pts with acute pancreatitis.
  • -Clin Gastro & Hep 2008; 6: 1070, 1077.   Fluids and imaging in acute pancreatitis.  With imaging, CT probably best.
  • – J Pediatrics 2008; 152: 106.  Acute pancreatitis in young children

Related blog entry:

Indomethacin to prevent post-ERCP pancreatitis

How much radiation from your CT scanner?

Posted on by

Our children’s hospital, along with many others, has made a concerted effort to reduce radiation exposure by adjusting CT scan settings.  Even a single abdominal CT scan may confer a small but real risk of developing cancer.  The trade-off with low-dose CT techniques has been a concern about poor image quality.  New research indicates that low-dose CT scan is not inferior to standard-dose CT with respect to detecting appendicitis (NEJM 2012; 366: 1596-605).

This single-center study examined 441 patients assigned in a single-blind fashion to low-dose CT (median dose: 116 mGy-cm) in comparison to 447 patients receiving a standard-dose CT (median dose: 521 mGy-cm).  All patients had CT for suspected appendicitis.  The negative appendectomy rate was 3.5% in the low-dose group and 3.2% in the standard-dose group.  There was no significant difference in appendiceal perforation rate or proportion of patients needing more imaging.

How much radiation do your patients receive with a CT scan?

Related newspaper article:

FDA issues guidelines to lower radiation exposure in children:

http://www.ajc.com/health/child-sizing-radiation-doses-1434081.html

Related posts:

Magnetic resonance enterography for Crohn’s disease

More imaging needed?

Additional references:

  • -NEJM 2010; 363: 1, 4. Safety of CT.  Can have overdose of radiation and even standard doses could cause complications.  Also, a big issue is downstream unnecessary testing due to incidental findings.
  • -JPGN 2011; 52: 280. Documents high exposure to radiation in large IBD pediatric cohort.
  • -J Clin Gastroenterol 2011; 45: 34-39. High levels of ionizing radiation thru CT scan in pts with IBD.
  • -Pediatr Radiology 2002; 32: 217-313. Minimizing radiation exposure, risk/benefit of CT. Proceedings from conference.
  • -Pediatr Radiology 2002; 32: 700-706. Risk of CT for young child: ~ 1 in 1000 risk of fatal cancer later in life.

Proton pump inhibitors–infection risk with cirrhosis

Posted on by

In a previous post (The Medical Pendulum and Gastroesophageal Reflux), I note that enthusiasm for proton pump inhibitors has started to wane.  In addition, a significant number of reported of potential side effects were referenced.  Another potential adverse effect is increasing the rate of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis (Clin Gastroenterol Hepatol 2012; 10: 422-27).

This retrospective study examined 65 hospitalized cirrhotic patients with paracentesis-proven SBP between 2006-2009 and compared them to 65 contemporaneous hospitalized cirrhotic patients without SBP.   Patients with SBP had a higher incidence of use of PPI within previous 7 days: 71% versus 42%.  Of patients with SBP receiving PPI, the authors state that 68% did not have a documented indication for PPI use.

Additional references/previous posts:

  • –Treating reflux does not help asthma
  • -Risk of Hypomagnesemmia -2011. http://www.fda.gov/drugs/drugsafety/ucm245011.htm
  • –Gastroenterology 2010; 139: 1115.  Review of safety of PPIs.
  • –Gastroenterology 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
  • –Gastroenterology 2010; 138: 896-904. 5 yrs of PPI -no increase risk in hip/spine fx.
  • –Arch Intern Med 2010; 170: 765-71, 747 (ed). PPI not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
  • –Arch Intern Med 2010; 170: 772-8. PPIs increase risk of Clostridium difficile infection (hazard ratio 1.42 –42% increase in risk), n=1166.
  • –Arch Intern Med 2010; 170: 784-90. n=101,796. OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.
  • –Clin Gastro & Hep 2010; 8: 504. Increased bacterial overgrowth with PPI use.
  • -JAMA 2009; 301: 2120-2128. Use of PPIs associated with INCREASED hospital acquired pneumonia by ~30%. Could result in 180,000 HAP cases/yr with ~33,000 deaths. n+ 63,878 admissions, 52% on PPIs or H2RAs (83% PPIs, 17% H2RAs). H2RAs NOT associated with HAP cases.

Does it make sense to look for parasites in RAP?

Posted on by

Probably not, in the absence of other symptoms.  A small study from Switzerland shows that treatment of Blastocystis hominis does not help recurrent abdominal pain (RAP) more than placebo (JPGN 2012; 54: 677-79).

This study result is not surprising.  A previous study of 157 RAP pediatric patients (JPGN 2007; 44: 524-26) showed that testing for ova and parasites was unnecessary as the incidence of parasitic infections in this population was not increased in RAP patients compared with controls. In this 2007 study, stool samples were positive for parasitic infection in 15 children, with no difference in prevalence between children with chronic abdominal pain (6/87; 7%) and healthy control children (9/70; 13%).

The current study had 37 patients complete the study.  The pain index (PI) for all patients improved in the study; however, there was no difference between patients who received antibiotics (trimethoprim-sulfa was used as first-line agent) compared to those who received placebo.

Regarding the methodology, the PI was either a visual analog scale with numbers from 0 to 10 or a standardized face scale; the specific scale was determined by the patient age.  Also, among the 20 patients who received antibiotics, 13 continued with B hominis in their stool tests after an initial round of therapy.  Yet the change in pain was virtually identical.  In antibiotic-treated patients, initial PI was 7.1.  After treatment, those with persistent B hominis detected in the stool had a PI of 4.2 whereas those with negative stool specimens had a PI of 4.1.  The placebo patients started with a PI of 7.4; after placebo treatment, a similar proportion cleared the B hominis from their stool –in this group, at the conclusion of the placebo treatment the PI was 2.4; the placebo group with persistent detection of B hominis had a PI of 3.2 at the conclusion of the study.

Although the potential pathogenicity of B hominis in humans remains unclear, it is not unusual in clinical practice for patients with this finding to receive treatment.   Besides trimethoprim-sulfa, metronidazole is frequently administered. Based on this study, placebo would be as helpful as an antibiotic in improving clinical symptoms.

Related blog entries:

What to make of FODMAPs

Pain changes brain

Disease modifying treatment in IBD

Posted on by

As noted in this blog (Only one chance to make first impression) and other sites as well, many have argued for early “top down” treatment to try to modify the natural history of Crohn’s disease (CD).  Early in the course of CD when an inflammatory process predominates, theoretically, treatment at this time point can prevent the development of intestinal fibrosis/strictured IBD phenotype.

Support for this approach can now be extrapolated from a mouse model as well (Inflamm Bowel Dis 2012; 18: 460-71).  In this study, the authors eliminated an inflammatory stimulus, Salmonella typhimurium, with levofloxacin treatment.  Treatment was initiated at sequential time points during infection.  Subsequently, the effects of the inflammation on the development of fibrosis was determined by examining histopathology; in addition, the effects on mRNA expression and protein expression were determined.  The time course of a number of cytokines is followed including TNFα, TGFβ, IL12p40, IL-17, IL-1β, and IL-6. While intestinal fibrosis developed even in those with early treatment, early treatment lessened, but did not eliminate, the development of fibrosis.

Since no effective antifibrotics exist and fibrosis may autopropagate even in the absence of inflammation, the authors postulate that early effective treatment has the best opportunity to alter the natural history.

Indomethacin to prevent post-ERCP pancreatitis

Posted on by

“Take two and call me in the morning” may now apply to the use of indomethacin in preventing post-ERCP pancreatitis.  A multicenter, randomized, placebo-controlled, double-blind clinical trial has shown that rectal indomethacin (two 50 mg suppositories) can reduce the rate of post-ERCP pancreatitis (NEJM 2012; 366: 1414-22).

A total of 602 adult patients were enrolled.  Patient selection favored those at increased risk for post-ERCP pancreatitis (eg. suspicion of sphincter of Oddi dysfunction) and excluded those at low risk for this complication (eg. routine biliary stent exchange, chronic calcific pancreatitis, or a pancreatic head mass).  Other exclusion criteria included active pancreatitis, elevated creatinine (>1.4 mg/dL), active peptic ulcer disease, and those already receiving a NSAID.

The suppositories (or placebo) were administered immediately after ERCP while the patient remained in the procedure room.

Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in indomethacin group and in 52 of 307 patients (16.9%) in placebo group.  In addition, moderate-to-severe pancreatitis was reduced as well 4.4% compared with 8.8% respectively.  In addition, there were no increased adverse events in the treatment arm; there was no increased risk of bleeding in particular.

While the mechanism of improvement is unclear, NSAIDs are potent inhibitors of phospholipase A2, cyclooxygenase, and neutrophil-endothelial interactions, all of which are known to play a role in the pathogenesis of acute pancreatitis.

Additional references:

  • -Am J Gastroenterol 2007; 102: 978-83.  Use of indomethacin to reduce pancreatitis after ERCP
  • -Gut 2008; 57: 1262-7.  Meta-analysis of rectal NSAIDs to prevent post-ERCP pancreatitis