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Food as medicine

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Two recent articles add some useful information regarding enteral therapy for Crohn’s disease (Inflamm Bowel Dis 2012; 18: 246-53 & JPGN 2012; 54: 298-305).

The first article enrolled 34 children with newly-diagnosed Crohn’s disease.  Patients were divided into elemental and polymeric formula groups and followed in a prospective, double-blind randomized controlled trial for two years.  Measures of improvement included the PCDAI as well as fecal calprotectin and fatty acids.  Both groups of patients responded clinically.  93% (14/15) of the elemental formula group achieved remission based on PCDAI scores (<11) and 79% (15/19) of the polymeric formula group.  The initial treatment was use of formula (along with only clears) either by NG or oral for 6 weeks.  All patients had NG placed at time of endoscopy and if sufficient oral intake was demonstrated (for 2 days), NG was removed.  All subjects had small bowel and colonic disease.  Although calprotectin levels decreased, they remained very elevated.  In the EF group, the median calprotectin dropped from 2023 μ/g to 1113 μ/g, though only one patient had a level below 400; similarly in the PF group the calprotectin dropped from 1929 μ/g to 1134 μ/g, and only two patients had a level below 400.  Some to the reasons why changes in diet may be useful have been alluded to in a previous post: Eat your veggies…if you don’t want to get sick.

The second reference is a clinical guideline on the use of exclusive enteral nutrition EEN).  The introduction notes that 65% of European pediatric gastroenterologists use EEN compared to 4% for North American pediatric gastroenterologists.  In pediatric trials, EEN and corticosteroids were considered ‘equally effective’ in a pediatric meta-analysis which included five randomized controlled trials (n=147).  However, a Cochrane review favored corticosteroid treatment over EEN in a meta-analysis that included adult and pediatric patients (n=192 EEN, n=160 corticosteroids).  According to the authors, small studies have demonstrated other potential advantages of EEN including higher rates of mucosal healing and better linear growth.  With regard to mucosal healing, the initial cited study casts with ongoing elevated calprotectin indicates that this does not occur in the majority of children with EEN therapy.  Other caveats:

  • Disease location: some evidence favors small bowel disease rather than colonic disease
  • Formula composition: does not seem to matter whether elemental or polymeric
  • Duration of therapy: majority treat for 6-8 weeks of EEN.  The authors recommend at least 8 weeks
  • Time for response: Inflammatory markers improve in a little as a week, remission typically 2-4 weeks
  • Concomitant medications: many places initiate immunomodulator treatment; others cycle EEN
  • Start with goal 120% of ‘maintenance’ nutrient needs.  On 1st day, authors recommend starting at 1/2 goal volume and gradually increase over 1-2 days
  • Partial enteral nutrition (PEN) (eg. overnight feedings & normal daytime diet) has been helpful in improving growth and may improve remission rates.
Why not EEN or PEN? Potential barriers include cost, difficulty changing diet, fear of tube feedings, and more acceptable alternatives.  At the same time, some of these barriers could be overcome.  Quality of life measures have improved in children receiving enteral nutrition.

The use of more top-down therapy may affect all of the above considerations (Only one chance to make first impression).

Additional references:

  • -Cochrane Database Syst Rev 2007; CD000542.  Enteral nutritional therapy vs corticosteroids to induce remission in Crohn’s disease.
  • -Gastroenterology 2011; 141: 742. AGA guidelines on use of enteral nutrition in wide variety of conditions.
  • -Gastroenterology 2008; 135 : 1005. omega-3 fatty acids ineffective in Crohn’s dz for maintaining remission.
  • -Pediatr Res 2007; 61: 356-60.  Enteral nutrition effect on protein turnover in adolescents with Crohn’s disease.
  • -J Pediatr 2000; 136: 285-91. Nutritional Rx w polymeric diet is effective w/in 8 weeks in 32/37.
  • -Scand J Gastro 2001; 36: 383-8. Elemental & polymeric diets successful in maintaining remission in ~43% of adults with complete steroid withdrawal
  • -JPEN 1992; 16: 499. improved wt,ht, decreased prednisone, decreased CDAI
  • -JPGN 2000; 31 (supp 2) A291. Polymeric vs elemental diet.
  • -JPGN 2002; 35: 339-40. Lactase deficiency – same prevalence in IBD as in RAP.
  • -JPGN 2000; 31: 3 & 8. EN about as effective as steroids for primary Rx.

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.