Author Archives: gutsandgrowth

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About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

Minimizing malnutrition in Biliary Atresia

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A retrospective study in Liver Transplantation reviews a single center experience with the use of parenteral nutrition (PN) in patients with end-stage liver disease due to biliary atresia (Liver Transpl 2012; 18: 121-129).  In this study which spanned the past twenty years, 25 PN BA patients were compared to 22 non-PN BA patients –all patients were younger than 36 months.  PN was started when maximal enteral nutrition failed to improve markers of malnutrition (triceps skinfold thickness, & mid-arm circumference).  Among the PN BA patients, there was a higher gastrointestinal bleeding rate and ascites; however, there was no difference in the rates of bacteremia, length of intensive care unit stay after liver transplantation, or patient/graft survival.  The authors speculate that the outcome for the PN BA patients would have been much worse without the PN as malnourished BA patients are at increased risk for graft failure and post-transplant complications.  It is noteworthy that PN patients did have progression of their liver disease that seemed to accelerate with the administration of PN, perhaps due to PN-associated cholestasis.  Specific changes included higher bilirubin levels, lower platelet counts, worsened coagulopathy, and higher calculated PELD scores.

Additional References:

  • Hepatology 2007; 46: 1632-38.  Growth failure and outcomes in infants with BA.
  • J Pediatr 2005; 147: 180-85.  Outcomes of 755 BA patients listed for liver transplantation.

Why are we seeing so many more cases

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In this month’s Gastroenterology, two articles offer some insight into this question for two separate problems.

With regard to inflammatory bowel disease, (IBD) –both Crohn’s disease and UC –there is an increasing prevalence and incidence worldwide (Gastroenterology 2012; 142: 46-54). This article identified 8444 previous citations and then identified 262 studies with relevant data.  Overall, the highest incidence and prevalence of these disorders occurs in Europe and North America.  In North America, Canada has the highest prevalence with 0.6% of the population having IBD.

After going through the statistics, the authors offer some discussion on why IBD is increasing.  In the developing parts of the world, some of the increase is due to the ability to detect and differentiate these disorders due to improving access to medical care/colonoscopy.  In the areas of the world with the highest incidence/prevalence, environmental risk factors are playing an important role.  Potential factors include microbial exposures, sanitation, lifestyle behaviors, medications, and pollution.  These factors are supported by other epidemiological studies which show that individuals who move from low prevalence areas to higher ones are at increased risk for IBD, especially among first generation children (Gut 2008; 57: 1185-91).  Furthermore, in low prevalence regions, IBD is increasing with more industrialization (Chin J Dig Dis 2005; 6: 175-81, Indian J Gastroenterol 2005; 24: 23-24.)  Exact mechanisms are poorly understood; however, even in the U.S. it is recognized that rural/farm exposure at a young age reduces the likelihood of developing IBD at a later age (Pediatrics 2007; 120: 354).

Celiac disease, likewise, has seen an increase in prevalence.  With celiac disease, the proliferation of widely available and more accurate serology has been crucial in the identification of more patients.  However, like IBD, there is likely a role for changing microbial environment contributing to an increasing case burden.  Recently, reports have shown that the risk of celiac disease can be influenced at birth (Gastroenterology 2012; 142: 39-45).  Although the absolute risk was modest, there was an increased risk demonstrated with elective but not emergent cesarean delivery among a large nationwide case-control study from Sweden.  Among the cohort of 11,749 offspring with biopsy-proven celiac (with matched control group of 53,887), elective cesarean delivery resulted in an odds ratio of 1.15 (confidence intervals 1.04-1.26).  This study confirmed other studies which have shown an increased risk with cesarean delivery (Pediatrics 2010; 125: e1433-e1440).  Some of the strengths of this Swedish study, included the fact that the deliveries were separated based on elective or emergency cesarean delivery and were controlled for whether the mother had celiac disease.  (Pregnant women with celiac disease have an increased risk of cesarean delivery.)  The authors speculate that the reason why elective cesarean deliveries increase the risk of celiac disease is that microbial exposures at birth likely influences perinatal colonization –>affects intestinal immune response and mucosal barrier function. Offspring of women with emergency cesarean delivery would be more likely to be exposed to bacteria from the birth canal and no significant increase risk of celiac disease could be identified in this group.

Thus how we are born and where we live make a big impact on the likelihood of developing these GI disorders.

Additional References:

  • -Gut 2011; 60: 49-54. n=577,627 Danish children. Use of antibiotics associated with increase risk of Crohn’s disease (but not UC), especially at younger ages (3-11month of age, & 2-3yrs of age). Each course increased risk by 18%. In children with >7 courses, relative risk was 7.3. especially penicillins.
  • -NEJM 2011; 364: 701, 769. Living on a farm decreases risk of childhood asthma.
  • -Nature 2011; 476: 393. ‘Stop killing beneficial bacteria.’  For example, killing H pylori likely increases risk of esophageal adenocarcinoma
  • -Gastroenterology 2011; 141: 28, 208. GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -Gastroenterology 2010; 139: 1816, 1844. Microbiome & affect on IBD vs mucosal homeostasis
  • -J Pediatr 2010; 157: 240. Microbiota in pediatric IBD -increased E coli and decreased F praunsitzil in IBD pts.
  • -J Pediatr 2009; 155: 781. early child care exposures lessens risk for asthma.
  • -IBD 2008; 14: 575.  Role of E coli in Crohn’s
  • -Lab Invest 2007; 87: 1042-1054. Role of E coli in Crohn’s
  • -Pediatrics 2007; 120: 354. Crohn’s less common after repeated exposure to farm animals in 1st year of life.

More practical information and links to other websites can be found at http://www.gicareforkids.com.

Diagnostic tests hardly ever help patients poop

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Virtually everyday pediatric gastroenterologists like myself see children with constipation problems; managing constipation is often a Sisyphean task.  Recent articles (JPGN 2011; 53: S2: 49, 55) reiterate what all pediatric gastroenterologists already know –constipation is almost always a management problem and only rarely a diagnostic problem.  Rarely do children with constipation need diagnostic tests.  These articles recommend testing only if alarm features are present, including the following:

  • Delayed meconium passage at birth
  • Bilious vomiting
  • Bloody stools
  • Fever
  • Bladder disorders
  • Poor response to conventional treatment
  • Abnormal exam

Additionally, these articles state that about 25% of functional constipation problems may persist into adulthood.  Among the patients who respond poorly to treatment, constipation, especially if associated with soiling (aka. encopresis), can be very detrimental for obvious social reasons.  This group of patients can be very challenging.  Many of the patients do not perceive the problem to be as severe as their parents and may be unwilling to work on fixing the problem.

Clinical experience has been that younger children respond better than older children. Perhaps, this is due to a greater ease of imposing a specific treatment plan in younger children along with the fact that the physiological and behavioral changes associated with chronic constipation are not as well-established.

Other pertinent aspects of treatment and diagnosis include the following:

Abdominal xrays are not very helpful (JPGN 2010; 51: 155.) and should mainly be reserved for those in whom a rectal examination cannot adequately be performed, such as very uncooperative patients, and in patients with concerns about abuse (or concerns about psychologic impact of exam).

Also, despite earlier reports of potential sacral abnormalities in children with chronic constipation or non-retentive soiling, a fairly large prospective MRI study (J Pediatr 2010; 156: 461-5) (n=158) found that only 3% had lumbar sacral abnormalities and none required neurosurgery (1 with spina bifida occulta, 3 with terminal filum lipomas).

In addition to the scholarly references below, some useful practical sources of information can be identified by going to my office website, http://www.gicareforkids.com and clicking “constipation.”

Additional references:

  • -JPGN 2011;52: 574.  n=117.  Describes outcome with placement of a cecostomy/appendicostomy for irrigations of colon.  69% success with antegrade enemas.
  • -Gastroenterology 2009; 137: 1963. Increased rectal compliance not associated with treatment response.
  • -J Pediatr 2009; 154: 258. Constipation associated with 3-fold increase in health utilization/cost.
  • -Clin Gastro Hep 2009; 7: 20. Review of complications associated with constipation in adults.
  • -Pediatrics 2008; 121: e1334. In this study, behavioral therapy was ineffective in treating childhood constipation.
  • -JPGN 2007; 44: 5.  Review of nonretentive fecal incontinence.
  • -J Pediatr 2006; 148: 62. Higher compliance is noted in children with functional fecal retention/encopresis; thus, larger stool volume need to reach intrarectal pressure of the urge to defecate.
  • -J Pediatr 2005; 147: 700-04.  69% of infants with constipation recovered within 6 months (then 15% relapsed).
  • -Gastrointestinal Endoscopy 2004;  60(1):39–43.  A new technique for management of intractable constipation in children: percutaneous endoscopic colostomy of the left colon
  • -JPGN 2004; 38: 75.  Colostomy in 10 children with intractable constipation.
  • -J Clin Gastro 2003; 36: 386-389.  Safety of stimulants for long-term use.
  • -Am J Gastro 2005; 100: 232-242. Myths about constipation. Stimulants have not been proven to cause a “cathartic colon”
  • -JPGN 2004; 39: 448. review
  • -J Peds 2004; 145: 409. 8/88 patients with intractable constipation with spinal cord lesions (6 with tethered cords). 6/7 better p surgery. Intractable was defined as  <2BMs/week x 3 months despite laxative treatment. Only one patient had physical exam finding.  This was a retrospective study.
  • -Gastroenterology 2003; 125: 357. Long-term constipation followup.  One-third had persistent constipation; 60% better at 1 year. (tertiary referral group)
  • -Pediatrics 2004; 113: 1753 & e520. When constipation & toileting difficulties both occur, constipation usually precedes toileting problems.
  • -NEJM 2003; 349: 1360.  Review.
  • -Arch Pediatr Adolesc Med 1999; 153: 377.  Digital exam  performed in only 23% at time of referral to specialist.

 

 

Drink Up!

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Green tea and coffee have a lot of advocates and a number of articles suggest that each can have beneficial effects for the liver.  This month’s Hepatology describes how a green tea component, epigallocatechin-3-gallate (EGCG), inhibits hepatitis C viral (HCV) entry. ECGC acts by blocking viral attachment to target cells with all HCV genotypes; it does not affect viral replication.  Other components of green tea do not have this effect.  A complete description of green tea components is described in the discussion of the article, Hepatology 2012: 54: 1947-55.  Also, there have been preliminary dosing studies in healthy volunteers which have shown that EGCG is safe at doses of 800mg daily for four weeks.  This would be the equivalent of drinking 8-16 cups of green tea per day (Clin Cancer Res 2003; 9: 3312-19).  In order to eliminate HCV, however, even higher amounts of EGCG would be likely.

 

Coffee also has been studied and has been associated with decreasing liver fibrosis.  In addition, coffee may enhance response to HCV treatments.  To my knowledge, there have not been extensive studies of either coffee or green tea for pediatric patients.

Additional References:

  • -Gastroenterology 2011; 140: 1961. Coffee (3 cups/day) increases response to PEG/RBV in HCV
  • -Hepatology 2009; 51: 201. Coffee decreases fibrosis. n=177.
  • -Hepatology 2009; 50: 1360. Coffee intake associated with slower progression of HCV liver disease
  • -Hepatology 2009; 50: 970. Coffee -2 cups per day decreases risk of liver fibrosis & HCC. Coffee has methylxanthin which inhibits connective tissue growth factor.

It’s often elemental

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A recent post on the pediatric GI listserv (GI Bulletin Board) this past month discussed protracted diarrhea of infancy.  The posting noted that this was a frequent problem that would hospitalize infants (in the first 6 months of life) for weeks & often would require parenteral nutrition.   “The cause of protracted diarrhea of infancy is usually ill-defined and is characterized by chronic nutritional failure, septic complications, and a high mortality.” ( Am J Dis Child 1973:125:358-364).  The availability of elemental diets have made this problem quite infrequent.  These infants often improve quickly, even with severe diarrhea.
Congenital diarrhea, rather than acquired diarrhea, remains much more of a challenge.  However, our understanding has improved a great deal in the past two decades.  My approach in this area relies a lot on the teachings I received as a fellow and from articles in the literature, especially the work of Dr. Martín.
For congenital diarrhea, my approach & differential diagnosis  are as noted below:
Approach:
1. Measure inputs/outputs for carefully –may need to use rectal ‘ng tube’ to assess stool output.  Check stool electrolytes.  Careful IVFs needed.
2. Trial of neocate (contains glucose polymer) excludes congenital lactase deficiency/most disaccharidase deficiencies.
3. Trial of RCF excludes glucose-galactose malabsorption.
4. The, remaining cases are considered protracted diarrhea of infancy (PDI):
  • PDI with normal villi: consider congenital chloride diarrhea, congenital sodium, sodium co-transporter deficiencies, heparan sulphate deficiency, glycosylation defect, neurogenin-3, congenital short gut.
  • PDI with abnormal villii/villous atrophy: post-infectious, autoimmune/allergic enteropathies, IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked).  If villous atrophy w/o inflammation, consider microvillus inclusion disease and tufting enteropathy.
DDx/specific entities to consider with congenital diarrhea:
1-Microvillus inclusion disease- An experienced pathologist should be able to establish this diagnosis with EM.
2-Congenital Na diarrhea –  these patients have a high volume secretory diarrhea that is very alkaline and contains high concentrations of the Na+.
3-Congenital disorder of glycosylation- in the absence of PLE, this should be taken off the list.
4-Glucose-galactose malabsorption-  all the GGM patients should have (at least at some point) +4 clinitest.   An RCF (Ross Carbohydrate Free) trial is a wonderful screen for GGM as the stool output will go to the normal range without carbohydrates.  It should be noted that sucrase-isomaltase deficiency improves with RCF as well.
5-Congenital enterokinase deficiency- if the child’s diarrhea persists while
on Neocate, you have essentially ruled out this disorder.
6-Autoimmune enteropathy -consider if the diarrhea is secretory
in nature; look specifically at the intraepithelial (normal in IPEX), lamina propria (increased number of CD8 and CD4 in IPEX) lymphocytes. IPEX is also associated with increased mucosal eosinophils. Also, serum IgE level is usually very high in IPEX patients. If there is  any evidence of glucose intolerance, check for anti-islet cell antibodies.
7-Ileal bile acid receptor defect- The diarrhea is generally in character
and is exacerbated with addition of dietary fats. The diarrhea should
improve with a trial of cholestyramine and a low fat diet.  Bile acid
absorption by the ileum may be measured using the bile acid analogue
75Se-homocholic acid-taurine test. (give a trial of cholestyramine if
75Se-homocholic acid-taurine testing is not available.)
8- Congenital chloride diarrhea (CCD)- Probably the most common congenital
diarrhea-these patients generally have fecal chloride concentrations that
exceeds the concentration of cations (Na+ and K+).
9- Chylomicron retention disease- You can certainly rule this out by H&E as
enterocytes are laden with fat.  However, this can be missed this if patient is fasted for a prolonged period of time before the biopsy was taken.  Interestingly, unlike all other enterocyte specific congenital diarrhea, this disorder will be accompanied by carbohydrate and AA malabsorption while on a fat containing enteral diet.
10. Mutant neurogenin-3- check immunostains on the small intestinal, colonic biopsies for chromogranin A to see if there is a paucity or agenesis of the enterochromaffin cells.  At UCLA, they are actively performing DNA sequencing for this disorder and can have results within a week. If this is needed, contact Dr. Martín & he can send a copy of the UCLA approved IRB form and a kit to isolate DNA from saliva.
Contact info: Martín G. Martín M.D., M.P.P.
Professor of Pediatric Gastroenterology and Nutrition
Director of the UCLA Center for Pediatric Diarrheal Diseases
David Geffen School of Medicine at UCLA
Mattel Children’s Hospital at UCLA
Box 951752
Los Angeles, CA 90095-1752
Phone: 310-794-5532; Fax: 310-206-0203
11.  In older infants, consider: Lysinuric protein intolerance -LPI is an inborn error of metabolism caused by defective transport of cationic amino acids at the basolateral membrane of enterocytes and renal tubular cells.  Typically presents after weaning from breast milk or formula.
12. Sucrase-isomaltase deficiency -these infants improve with lactose-containing formula.  May present after a gastroenteritis when they are switched from a standard formula or breastmilk.
Additional References:
  • -J Peds 2008; 153: 586.  case report of congenital chloride diarrhea with useful references.
  • -J Pediatr 2007; 150: 198.  Review.  Newborn with diarrhea.
  • -NEJM 2006; 355: 270, 236 (editorial).  mutant neurogenin-3.  This defect result in diarrhea with all substances except water.  Lack of enteroendocrine cells on biopsy.
  • -JPGN 2004; 38: 16 (invited review of neonatal enteropathies)
  • -JPGN 1999; 28: 137.  Sucrase-isomaltase.

Looking for trouble

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Although cirrhosis is an infrequent problem in pediatric gastroenterology, there are several important management aspects.  One of these is surveillance for hepatocellular carcinoma (HCC).  In this month’s Hepatology, Poustchi et al describe the “feasibility of a randomized control trial for liver cancer screening” (Hepatology 2012; 54: 1998 & editorial 1898).  Not surprisingly, the authors conclude that such a trial is not possible with informed consent.  As such, the effectiveness and cost-effectiveness may not be determined.  Although the consensus is in favor of screening, there are potential disadvantages like discovering non-cancer nodules leading towards unnecessary invasive investigations.

The AASLD considers screening for HCC worthwhile in patients with cirrhosis.  When HCC is discovered early, treatment can be effective.  For example, if HCC meets Milan criteria–either 1 tumor <5cm or 2-3 < 3 cm each– OLT has 91% 1 yr survival.

Most U.S. physicians (74%) report that they screen all of their patients with cirrhosis; however,  population-based studies of Medicare patients show only 6.6% receive regular surveillance (Hepatology 2010; 52: 132-41) & only 12% of veterans with HCV-infected cirrhosis (Ann Intern Med 2011; 154: 85-93).  Better ways of consolidating screening can bridge this gap & perhaps catch cases of HCC amenable to treatment.  This may be another area where an EMR can help with patient/doctor reminders.

Current practice recommendations for cirrhotic patients: Ultrasound every 6 months (with or without AFP).  This recommendation is supported by the AASLD, EASL, and APASL.  The efficacy of HCC surveillance is reviewed further in the January “Education Practice” article: Clin Gastro & Hepatatol 2012: 10: 16-21.

Additional references:

  • Gastroenterology 2011; 141: 1240. Risk of HCC from HBV related to ALT and HBV DNA levels.
  • NEJM 2011; 365: 1118. Review. For cirrhotics/advanced liver dz, recs U/S & AFP q6-12months.
  • Hepatology 2010; 53: 1020. updated guidelines from AASLD. Suggests U/S as screen q6months.
  • J Pediatr 2011; 159: 617. BA associated with HCC.
  • Hepatology 2010; 51: 1972. NASH cirrhosis pts develop HCC. 12.8% over .32 yrs (compared with 20.3 % of pts with HCV cirrhosis). Alcohol & age were independent variables that increased risk.
  • Gastroenterology 2009; 137: 110, editorial page 26. AFP has at best 66% sensitivity for HCC.
  • Gastroenterology 2009; 136: 138, 39(ed). HCC occuring c HCV ~1%/yr in HALT-C study. prolonged Rx -not helpful. n=1005. Best surveillance is US. Only 60% of pts c HCC received surveillance. Hepatolgy 2005; 42 : 1208.
  • Gastroenterologyo 2008; 135: 111. DM & obesity associated with increase risk of HCC in patients with HBV/HCV.
  • Gastroenterology 2008; 134: 1612. Increasing LTx for HCC affects others on Tx list.
  • Gastroenterology 2007; 132: 2557. review
  • Clin Gastro & Hep 2006; 4: 252 Review.
  • Hepatology 2005; 42: 1208. AASLD guidelines for management.
  • Gastroenterology 2004 (November) 127; supplement 1:S1–S323. Review of HCC. S108: screen with alpha-fetoprotein AND U/S every 6-12 months in individuals with cirrhosis or advanced disease (not needed in individuals with mild disease).
  • Clinical Gastro & Hep 2003; 1: 10-18. Review.
  • Gastroenterology 2004; 126: 1005. HCC survival improved when detected as part of surveillance.

Only one chance to make first impression

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Infliximab (IFX) came into clinical practice in 1998 after impressive results, published in the New England Journal of Medicine, demonstrated remarkable success in refractory Crohn’s disease  and even allowed resolution of fistulas.  Due to its expense and perceived risks, IFX has been typically reserved for treatment failures & significant perianal disease.  Although there have been discussions about ‘top-down’ therapy for many years, more and more it has become apparent that the best opportunity to influence the natural history of Crohn’s disease is early in the course; and perhaps in some cases of ulcerative colitis early IFX treatment may be worthwhile.  Clinical experience and treatment trials have shown that IFX response is significantly greater in Crohn’s disease than ulcerative colitis.  
Data on the postoperative course of Crohn’s disease has been informative on this approach as have large studies demonstrating that IFX is likely at least as safe as any other medication treatments for moderate-to-severe disease (eg. thiopurines, corticosteroids, methotrexate, tacrolimus).  With regard to postoperative Crohn’s disease, it has been shown that microscopic disease may develop within one week of intestinal resection.  More than 70% of postoperative patients develop significant mucosal recurrence within 12months (i2 or greater); yet, symptoms may not develop for a much longer time.  When significant mucosal disease is present, it may already be too late to achieve optimal response to IFX and similar agents due to remodeling of the intestinal submucosa.  Early in the course of Crohn’s disease, the vast majority of patients have an inflammatory phenotype (Cosnes J, et al. Inflamm Bowel Dis. 2002; 8:244-25), whereas later in the course, stricturing and penetrating disease are increasingly common.  

Postoperative mucosal scoring system:

• i1 – 5 or fewer apthous lesions

• i2 – more than 5 apthous ulcers with normal mucosa between, or skip areas of larger lesions

• i3 – diffuse apthous ileitis with diffusely inflamed mucosa

• i4 – diffuse inflammation with large ulcers, nodules or narrowing

 Rutgeerts et al. Gastroenterology 1990;99:956-83

Top-down approach:

Benefits: higher efficacy, lower disease-related complications, decrease surgery, improvement in catchup growth/bone formation (both not shown in AZA trials)

Risks: higher costs (but probably cost-effective)

**IFX therapy early may save health care costs by reducing surgery/hospitalizations:  Jewell DP et al, Eur J Gastroenterol Hepatol 2005, Leombruno JP et al Pharmacoepidemiol Drug Saf 2011

Conventional approach with accelerated step-up:

Risks: lower efficacy, higher infection risk/mortality with repeated steroids

Benefits: possibly lower cost

Potential drawbacks with azathioprine or 6-mercaptopurine (thiopurine class):

  • IBD 2011; 17: 2138. AZA can achieve remission in only ~30%.
  • Canc Research 2009; 69: 7004.  AZA is carcinogen– incorporated into DNA & changes sun absorption.  Skin cancer risk never drops when stopping med.
  • Gastro 2011; 141: 1621: CESAME (n=19,486)  thiopurines associated with NHL risk.  HR 5.28.
**Much of the information on this posting was influenced by presentations at “Advances in IBD 2011.”  Specific speakers that influenced this posting include Robert Baldassano, Marla Dubinsky, and Miguel Regueiro.

Additional References:

  • IBD 2009; 15: 1583. Postoperative mgt: low risk (1st surg, short stricture) –>no Rx; moderate risk (<10yrs of dz, long stricture, inflammatory dz)–>6MP; high risk (penetrating dz, >2 surg) –>IFX.  Post-op scope @6-12mo
  • JPGN 2009; 48 suppl 2: S72
  • Clin Gastro & Hep 2009; 7:183. Long term results with surgery for small bowel Crohn’s. n=865 surgeries. Risk for repeat surgeries: younger age, upper small bowel location, stricturing
  • Gastroenterology 2009; 136: 441. IFX prevents recurrent Crohn’s post-op. n=24. 1/11 w recurrence vs 11/13 control patients.
  • Am J Gastro 2008; 103: S412 (abstract 1054) IFX reduces post-op recurrence. clinical recurrence 0% at week 54 vs 39% of controls. n=23. 90% in IFX group with endoscopic remission vs 15% of placebo group.
  • Lancet 2008; 371: 660-667.   top-down strategy more likely to achieve endoscopic remicssion after 2yrs: 73% vs 30%. n=129.
  • NEJM 2010; 362: 1383. Sonic study. Combination AZA/IFX with greater efficacy. 56.8% remission in combo Rx vs IFX monotherapy.
  • Gut 2010; 59: 1363.   n=121.  Co-treatment helpd reduce complications & flares relative to monotherapy (& azathioprine appeared to be more effective than methotrexate).
  • JPGN 2009; 49: 183.  REACH pediatric trial showed good perianal dz response to infliximab.

Deadly consequences of pain management

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A big part of a pediatric gastroenterologist’s daily practice is trying to help patients with recurrent abdominal pain.  The goals are to determine the reason for the pain and then to offer the best therapy.  In many cases, these goals can be quite difficult.  With regard to diagnosis, the majority of patients have ‘functional’ pain and the diagnosis is in part a diagnosis of exclusion, trying to rule out other potential etiologies.  With regard to treatment, this is also difficult.

Narcotics are not often given for pediatric abdominal pain, but are used under certain circumstances.  These medications can have unintended consequences.  One consequence of frequent narcotic usage is that individuals may tolerate pain more poorly after receiving narcotics.  A useful review of narcotic overuse was published in the New England Journal of Medicine in 2010.  (NEJM 2010; 363: 1981).

“Deaths from unintentional drug overdoses in the United States have been rising steeply since the early 1990s …and are the second-leading cause of accidental death, with 27,658 such deaths recorded in 2007.”  11,499 of the deaths in 2007 were due to unintentional narcotic overdose.  In comparison, in the same year, there were about 6,000 deaths from cocaine & 2,000 deaths from heroin.

Besides the number of deaths, the other alarming factor has been a sharp rise (10-fold since 1990) in the usage of narcotics in the past two decades.  One of the factors driving this increase has been a compassionate interest in relieving pain.  The availability of these drugs throughout the country even in remote regions allows these abusable drugs to be more accessible than illicit drugs like cocaine and heroin.   While the availability of these medications may increase the rates of suicide, most opioid-overdose deaths are tragic accidents. Often, laboratory tests identify one or more substances in addition to the opioid, indicating that the depressant effects of alcohol or other drugs were additive  in causing death.

With regard to gastroenterology/pediatric gastroenterology, another important aspect of narcotics use is the association of increased mortality risk with inflammatory bowel disease.  This has been shown by analyzing a registry for infliximab (IFX) (Lichtenstein G, DDW 2010, abstracts#T1039 & T1040.).  In the TREAT registry with 6273 patients (3334 treated with IFX), the only risk factors for increased mortality/increased infections were steroids and narcotics.  This study also showed that IFX did not increase mortality, serious infections, malignancy or lymphoma in this cohort.

Additional Reference:

Clin Gastro & Hep 2008; 6: 978. Refractory abdominal pain review.  ‘Narcotics over time increase frequency, duration and intensity of pain.’ Practical recommendations:
treat constipation, withdraw narcotics, consider mental health (CBT/hypnosis/psychotherapy/stress mgt), and possible TCA or SNRI therapy.

More evidence that breastfeeding improves cognitive development

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A large cohort study from the United Kingdom with 11,101 term infants and 778 preterm infants shows improved cognitive development when infants are breastfed.  J Pediatr 2012; 160: 25-32.  There have been a number of previous studies as well that have shown that breastfed children have an IQ that is ~5 points higher than nonbreastfed children; however, when adjustment for confounders, especially maternal education, this effect is weaker.  Since this is an observation study (randomized blinded study would be impossible), it is difficult to control for all variables.  Nevertheless, prolonged breastfeeding, more than 2 months in preterm and more than 4 months in term infants, is associated with higher cognitive development.

Additional references:

  • Am J Clin Nutr 199; 70: 525-35.
  • BMJ 2006;  333: 945.
  • Arch Gen Psychiatry 2008; 65: 578-84.
  • Paediatr Perinat Epidemiol 2003; 17: 81-90.

Other refences:

  • J Pediatr 2009; 155: 421.  Breastfeeding may have possible protective effect from developing inflammatory bowel disease.  Review of multiple studies.
  • J Pediatr 2002; 141: 764.  Breastfeeding may protect against obesity.
  • BMJ 2007; 335: 815-20.  Longer time of breastfeeding does not reduce allergy/asthma. n=17,046 pairs of mother-infant (13,889 followed up at age 6.5yrs)

The cost of progress in treating Hepatitis C

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Background information on Hepatitis C (HCV):

  • —170 million people worldwide infected with HCV, 2.7 milllion people in U.S. infected
  • —27% of worldwide cases of cirrhosis are due to HCV
  • —25% of cases of hepatocellular carcinoma are due to HCV
  • —Established treatment with pegylated interferon (PEG IFN) and ribavirin have ~40% response rates in genotype 1 (74% of HCV in U.S.) and relapses are not uncommon among responders

New treatments for Hepatitis C (in combination with previous treatments):

  • —Two new drugs: Boceprevir (BOC) & Telaprevir (TVR)
  • —Overall sustained viral response (SVR) with BOC combination 63-66% vs 73-79% with TVR combination treatment
  • —Both trials demonstrate marked improvement over previous
  • Mechanism of action: —Protease inhibitor binding to NS3 HCV target
  • —BOC: Wholesale cost $1100/week (20-44 weeks)
  • —TVR: 12weeks cost: $49,000
Previous treatments for hepatitis C typically cost about $5000 per month (http://www.familydrugguide.com/family/ub/view/Consumer_Reports_Health/526033/4/hepatitis_c_drugs).  The addition of these newer drugs could add another $50,000 to the cost of treatment.  In some cases which respond well to the newer treatments, shorter treatment periods will lower the increase in cost.  Although these drugs are expensive, they may be lifesaving and may obviate the need for liver transplantation.  Due to the potential complications of HCV, more medications are in the pipeline.  They may be easier to take but are likely to be expensive as well.  The safety & effectiveness of these medications have not been demonstrated in published pediatric studies.
Article References:
  • Hepatology 2011; 54: 1433.  Updated AASLD HCV treatment guidelines
  • NEJM 2011; 364: 1195-206, Editorial pg. 1272. Addition of boceprevir, in 1097 previously untreated pts increased SVR. In whites, 40%–>67% & in blacks from 23% –>42%. Medication given after lead-in of 4 weeks. More frequent anemia in boceprevir-treated patients (SPRINT-2 study).Boceprevir dosing: 800mg (4 capsules) TID with food. (trying to space out doses evenly).
  • NEJM 2011; 365: 1014. n=540. Telaprevir study: extended SVR 72%. In pts with rapid viral response (RVR) at 4 & 12 weeks (no detectable HCV), Telaprevir12weeksPegRbv24 was as effective as Telprevir12weeksPegRbv48. Dosing for study: Teleprevir 750mg TID, PEGalfa-2a 180mcg/wk, RBV1-1.2gm per day.  Rash in 37% (severe in 5%), anemia in 39% (severe in 6%).
  • NEJM 2011; 364: 2405, 2417, 2429 (review). Telaprevir addition:  up to 75% response in HCV genotype 1 pts. n=1095 in 1st study, n=833 in 2nd study (re-treatment study)
  • Gastroenterology 2011; 140: 746. Summary of results of boceprevir (used with IFN -alfa 2b 1.5/kg) & telaprevir (used with IFN -alfa 2a 180mcg). “Similar effectiveness” thus far. Telaprevir used for 12 weeks without lead-in period.  TVR: most frequent problem -rash & then anemia.  In practice, dosing in adults: Telaprevir will be used at 750mg TID in combination with IFN-2a 180mcg & RBV 1-1.2g/d. & used for 1st 12 weeks of Rx. This will allow ~50% of patients to have shorter Rx duration:  if HCV RNA RVR –>24week total vs 48week total in those w/o RVR.  Both drugs best for genotype 1.