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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.

 

 

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.

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.

Good News for Celiac Disease

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With the discovery of precise serologies to identify celiac disease, the likelihood of complications of celiac disease has been changing.  In addition, the presentation of celiac disease is different now.  Instead of seeing children with malabsorption and abdominal distention, many children and adults are identified with mild or no symptoms.  Also, the risk of severe complications including malignancy and autoimmune disease has been reevaluated based on larger cohorts.  Twenty years ago, the risk of these complications did serve as a motivator for continuation of a gluten free diet (GFD).   While a GFD remains important, these risks are much lower than previously reported.  The most recent article to support this contention is the following:

Clinical Gastroenterology and Hepatology 2012; 10: 30-36.  This study examined ~45,000 patients with either celiac disease (villous atrophy, Marsh score of 3), duodenal inflammation (Marsh 1 or 2), or latent celiac disease (normal mucosa & positive serology).  After the first year, there was no significant increase risk for GI cancers.  During the first year, cancers that were identified may not have been causally-related to celiac disease but due to coincident detection.

This article due to its large cohort is very useful, but other articles have come to different conclusions.  Irregardless, there are still compelling reasons to continue a GFD.  Many individuals feel better on a GFD & did not recognize prior symptoms.  Maintaining this diet probably lowers the risk of developing certain autoimmune conditions and definitely improves bone health.

Other recent &/or related articles:

–Gastroenterology 2010; 139: 763. Mortality NOT worsened in undiagnosed celiac disease (identified by review of serology) in Olmstead County, though bone density decreased. n=129 of 16,847. (?milder cases undiagnosed)
–J Pediatrics 2010; 157: 373, 353. Even patients without villous atrophy & positive serology, benefited from GFD with regard to GI symptoms and serological markers.
–JAMA 2009; 302: 1171-78. n=29,096. Mortalitiy increased in celiac disease: 35% for latent, 72% for inflammation, 39% for celiac dz.

–Clin Gastro & Hep 2008; 6: 753.  Incidence of autoimmune diseases less in those celiac patients who were compliant with GFD. n=178.

–Gastroenterology 2002; 123; 1428-1435. n=12,000.  Risk for cancer 1.3 odds ratio (lower than in previous studies).

The Medical Pendulum and Gastroesophageal Reflux

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In so many areas of pediatric gastroenterology, there is a gradual development of enthusiasm for a medical treatment.  In the vast majority, the enthusiasm goes too far and closer scrutiny often determines a more limited role for this medical treatment or potential adverse effects that were not initially appreciated.  The latest example of this may well be with the use of proton pump inhibitors (PPIs) for gastroesophageal reflux disease, particularly in infants and individuals with asthma.  Although these medications may not have reached their apogee, more and more their effectiveness for so many ailments has been questioned.  In this month’s issue of JPGN, this is highlighted (JPGN 2012; 54: 8-14).  The article which emanates from the offices of the FDA discusses the fact that the usage of PPIs has increased 11-fold from 2002-2009 in infants <12months of age; 404,000 prescriptions were dispensed to 145,000 infants in the U.S. in 2009.    At the same time, althougth there have been four randomized controlled trials of PPIs in infants, NO studies have demonstrated the effectiveness of these drugs in this population.  As a consequence, the authors recommend that these drugs be restricted to infants with endoscopically-proven GERD/erosive esophagitis.  No other tools are sufficient to identify infants who are likely to respond.  Perhaps the reason why these agents work less well in infants is due to the fact that acid secretion is much less in infants than in children and adults.  For example, at 4months of life, average acid secretion rate in infants is ~27-fold lower than in adults (Am J Dig Dis 1969; 14: 400-14). As a consequence, their symptoms may not be responsive to acid reduction treatments.

Other related references on GERD in infancy:

–JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placeblo in withdrawal rates due to lack of efficacy. n=128.
-NASPGHAN 2009, Abstract#21. Meds/Rx of NICU pts did not shorten hospital stay or promote wt gain, n=1149.
–JPGN 2009; 49: 498. NASPGHAN GERD guidelines. “In infants and toddlers, there is no symptom or symptom complex that is diagnositc of GERD or predicts response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatrics 2009; 154: 514-20.)-Reflux is “not a common cause of unexplained crying. irritability..in otherwise healthy infants.” “There is no evidence to support the empiric use of acid suppression for the treatment of irritable infants.”

GERD and respiratory/ENT issues:

–Gastroenterology 2010; 139: 1887. PPIs decreased postnasal drainage compared to placebo. n=75. (50% vs 5%) age discrepancy in patient populations.
–Clin Gastro & Hep 2010; 8: 741 (excellent editorial), 770 (article on rabeprazole improving heartburn Sx in pts with laryngitis), n=82. Editorial suggests 1-2month trial of BID PPI and if not effective, then little to offer. May change when studies looking at surgery (after impedance) outcomes.
–Gastroenterology 2010; 139: 754. 716 (editorial). Acoustic cough & reflux. Study recorded cough during pH measurement. n=71. ‘causality cannot be established until effective treatment’ available.
–Gastroenterology 2009; 137: 1844. Critical review of below NEJM article. ‘a subset of asthmatics will have objective detection of GERD without typical symptoms…work by Amer Lung Assn suggests that twice daily PPI will not be helpful’..however, ‘perhaps 3-6months of PPI may still be reasonable until we can accurately identify subgroups of pts who may respond.’ –Gary Falk, Cleveland Clinic
–NEJM 2009; 360: 1487, 1551. Use of PPIs (nexium 40mg bid) in poorly-controlled asthma with no symptoms of GER –did not help w asthma control & pH studies were not predictive of response. n=412 adults. 40% c abnl pH studies in each group (nexium vs. placebo).
–Clin Gastro & Hep 2007; 5: 1379. Review of ENT findings and reflux.
–Am J Gastro 2007; 102: 716. Poor specificity of ENT findings for diagnosis of laryngopharyngeal reflux.
–Aliment Pharm Ther 2007; 25: 385-92. meta-analysis. Rx c PPIs not more effective than placebo in resolving ENT symptoms presumed to be due to GER. Editorial suggests some patients may benefit, but better tools are needed to identify them.

GERD and surgery:

–Gastroenterology 2011; 141: 1938.  LOTUS study in JAMA summarized in this review. (JAMA 2011; 305: 1969) Medical treatment outperformed surgery. 92% under control (remission) with long term medical Rx vs 85% with surgery & fewer side effects of medical treatment.
–Clin Gastro & Hepatology 2009; 7: 1292, 1264 (editorial). 12yr outcomes for surgery vs PPI. n=154 omeprazole, n=144 surgery. Similar long term outcome ~50% with long term remission.

–Pediatrics 2006; 118:1828. 48,665 antireflux surgeries done from 1996-2003 (~7000/yr) in US

–Clin Gastro & Hep 2006; 4: 299. Frequent complications post-op and frequent need for GERD meds.  Dysphagia in 19%, dilatation in 6%, repeat surgery in 2%, mortality in 0.8% (n=3145). 50% required GERD meds.

–Clin Gastro & Hep 2004; 2: 978-984. Pediatric study.  n=198.  63% required post-op treatment for recurrent GERD -retrospective review 1996-99.

Proton Pump Inhibitors and reported adverse effects:

-Risk of Hypomagnesemmia -2011. http://www.fda.gov/drugs/drugsafety/ucm245011.htm
–NEJM 2010; 363: 2114. large Denmark study. 5082 fetuses with PPI exposure (out of 840,968 live births). Risk of birth defects NOT increased with exposure during 1st trimester. Possible slight increase risk with preconception use except with omeprazole.
–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. 5yrs of PPI -no increase risk in hip/spine fx.
–Arch Intern Med 2010; 170: 765-71, 747 (ed). PP 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.
–Gastroenterology 2009; 137: 80. PPIs induce acid-related symptoms in ~22% vs 7% of placebo in healthy volunteers.
–Ann Intern Med 2008; 149: 391-398. Risk for pneumonia associated with short-term PPI use, not long term
–Clin Gastro & Hep 2007; 5: 1418. Increases risk of bacterial gastroenteritis.
–JPGN 2007; 45: 395, 421. Increasing use of PPIs-4-fold from 2000-2003; 0.5% of all infants. No safety/efficacy data.
–J Pediatrics 2007; 150: 262. Long term use (up to 11yrs of usage) of PPIs in 166 children; minimal problems: 2 c nausea, 2 c skin rash, 1 c diarrhea, 1 c agitation.
–JAMA 2006; 296: 2947-53. Risk of bone fracture –odds ratio 1.44-2.65 with long-term PPI treatment (>1yr); UK study looked at 1.8million

Clostridium difficile -Current Battlelines

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The most recent how to treat Clostridium difficile with fecal microbiota transplantation is described in a review article, Clinical Gastroenterology & Hepatology; 2011: 9:1044-49.  This article details the rationale and effectiveness of this approach.  Indications include 2-3 recurrent episodes or moderate/severe episode not responding to conventional treatment. Workup for donors to minimize the risk of transmission is discussed.  The article points out that fecal transplantation can be accomplished by nasogastric or transpyloric tubes or can be delivered directly via colonoscope or via retention enema.

Additional information on this topic:

–Am J Gastro 2000; 95: 3283-5.
–Clin Inf Dis 2003; 36: 580-5.

More C difficile references:

  • –NEJM 2010; 364: 422, 473. Fidaxomicin – a macrocytic abx –more effective than vancomycin (92% vs. 90%) and with lower recurrence (15% vs 25%). Dose 200mg BID. n=629.
  • –NEJM 2010; 362: 197, 264 (editorial). 1st article: n=200. Rx with monoclonal antibodies (against toxins A & B) -single infusion (10mg/kg) –reduced recurrence rate from 25% vs 7% & among those with previous recurrence, the rate was reduced from 38% to 7%.
  • –NEJM 2011; 365: 1693. Host/pathogen factors. n=4143.
  • –Gastro 2009; 136: 1152, 1206. “reining in recurrent C. diff”
  • –JPGN 2009; 48 suppl 2: S63-65. Cohen MB. ~35% of patients now w/o antibiotic exposure.
  • –Curr Opin Gastro 2008; 25: 24-35. Use of sacchromyces boulardii(1gm/d)x 2 weeks w Vanco may reduce recurrence by >50&.
  • –Journal of Pediatrics 2009; 154: 607. n=198.  Virulent NAP1 strain present in~19% from 2 children’s hospitals.
  • –NEJM 2009; 360: 637. C diff (even toxigenic strains) present in ~50% of healthy newborns. Not convincingly associated with any illnesses in newborns –possibly due to lack of receptor in infants (J Clin Invest 1992; 90: 822-9).

 

Welcome to GutsandGrowth! My Background

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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.  I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems.

Currently, I am the 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 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, 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 15 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. For many families, more practical matters 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
– 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. I like to read, walk/hike, exercise, swim, and play tennis with my free time as well as go to baseball games.

I do not have any relationships with pharmaceutical companies or other financial relationships to disclose.

Eosinophilic Esophagitis -Six Food Group Diet

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One of the topics that continues to have a number of important articles each month is eosinophilic esophagitis. One of the most important recent articles is the following:
**Kagalwalla AF, et al. JPGN 2011;53: 145–149. Identification of Specific Foods Responsible for Inflammation in Children With Eosinophilic Esophagitis Successfully Treated With Empiric Elimination Diet.

Results: A total of 36/46 (25 M/11F) children who were initially successfully treated with SFED completed this trial; the mean age was 7.6 years. The most common foods identified were 25 to cow’s milk (74%), 8 to wheat (26%), 4 to eggs (17%), 3 to soy (10%), and 1 to peanut (6%). Milk was 8 times more likely to cause EoE compared with wheat, the next most common food (95% confidence interval 2.41–26.62, P1⁄4 0.0007).

Previous articles in this area include the following:
–Immunol Allergy Clin N Am; 2009; 29: 77-84. Review article.
–Clinical Gastroenterology & Hepatology 2006; 4: 1097.
–Clinical Gastroenterology & Hepatology 2006; 3: 1198.

These studies identify the divergent approaches to dietary treatment in patients with eosinophilic esophagitis. Some patients can be managed with elimination diet based on allergy testing. However, due to the difficulty of allergy testing and its potential flaws in this population, some patients need to resort to a so-called six-food group elimination diet (Milk, wheat, eggs, nuts, shellfish, and soy) and some even need a complete elemental diet. Almost all patients managed with dietary restriction require followup endoscopy to determine the effectiveness of this dietary approach. In subsequent posts, some of the references regarding medical treatments (eg. budesonide) and biomarkers will be reviewed.