Category Archives: Pediatric Gastroenterology Intestinal Disorder

Speed matters

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Capsule endoscopy is cool.  Like any technology, it has certain advantages and some shortcomings.  Understanding that this technology has limited sensitivity and specificity is an important matter in clinical practice.

The suboptimal sensitivity is apparent in a recent study (Am J Gastroenterology, (10 January 2012) | doi:10.1038/ajg.2011.461).  In this study titled, “Detection of Lesions During Capsule Endoscopy: Physician Performance Is Disappointing,” the authors compare the performance of 17 capsule endoscopists in reading clips from 24 capsule procedures.  18 of these clips were abnormal but only abnormal in <0.1% of frames.  They compared different reading modes, speeds and the experience of the physicians.  By using clips, they were able to truncate the sessions to a similar length as an individual capsule procedure.

Their findings showed detection rates of 69% for angioectasias, 38% for ulcers/erosions, 46% for masses/polyps, and 17% for blood.  For all categories the detection rate was ~45% for SingleView15, QuadView20, and QuadView30; however, SingleView25 had a 25% detection rate.  One surprising finding was how little experience mattered; there was no significant advantage in having more experience.  In fact, the best performer who correctly identified 78% of the abnormalities had read only 45 capsule studies previously; the worst performer with a 17% score had read more than 11,000 previously.

In a typical capsule study, 40,000-60,000 images are generated.  If there is not a diffuse disease, then the lesion may go undetected.  The findings of these studies, though limited by the small number of interpreting physicians, confirm problems with sensitivity from other studies.  One aspect of this study that deserves emphasis is that speed matters.  As with colonoscopy, additional time reviewing the study does increase the likelihood of identifying abnormalities.  Ultimately, technological innovation may improve the results with capsule endoscopy.  With newer versions of the software,  “suspected blood indicator” (SBI) quickly identified six of the 18 lesions and “QuickView” identified 11 of the 18 lesions.  As with any test, though, if the clinical suspicion is high, having another physician review the study or using an alternative imaging tool may be necessary.

Another problem to keep in mind with capsule endoscopy (or wireless capsule endoscopy -WCE) is that especially in adults there is a significant background abnormality rate that may be clinically unrelated (Clin Gastro & Hepatol 2005; 3: 133-141. n=413. 13.8% with baseline mucosal injury).

Additional references:

  • -IBD 2008; 14: 1219. Correlation of capsule & MRI enteroclysis. Capsule detected more mucosal lesions.
  • -JPGN 2008; 47: 31. Capsule endoscopy may reclassify pediatric IBD.
  • -Dig Liver Dis 2008; 40: 216-223. Study comparing capsule vs EGD in detecting varices.
  • -JPGN 2008; 46:4. Review.
  • -Gastroenterology 2007; 132: 855. Capsule outperforms push enteroscopy.
  • -IBD 2007; 13: 331. Role of WCE in IBD.
  • -Pediatrics 2006; 118: e904. Use of capsule endoscopy for HSP
  • -Clin Gastro & Hep 2005; 3: 959. WCE should be 2nd step in obscure bleed, p egd/col.
  • -Clin Gastro & Hep 2005; 3: 772. WCE outperforms enteroclysis in identifying Crohn’s sm bwl dz.
  • -Gastroenterology 2005; 128: 1172. NSAID injury witnessed in 68% of healthy volunteers p 2 week course; 75% c increased fecal calprotectin.
  • -Clin Gastro & Hepatol 2005; 3: 411. Practical applications & review.
  • -Clin Gastro & Hepatol 2005; 3: 264-70. Study of 30 children; helpful in diagnosing obscure bleeding.
  • -Endoscopy 2005; 37: 960-65. Results of capsule endoscopy trials
  • -Clin Gastro & Hepatol 2005; 3: 133-141. WCE to assess NSAID injury, n=413. 13.8% with baseline mucosal injury. Celebrex with fewer lesions than Naproxen plus omeprazole.
  • -Gortzak Y, Lantsberg L, Odes HS. Video capsule entrapped in a Meckel’s diverticulum. J Clin Gastro 2003; 37: 270-271.
  • -Clin Gastro & Hep 2005; 3: 55. visible lesions c NSAIDs
  • -IBD 2004;10: 278-285. WCE for Crohn’s (review) Capsule can help differentiate UC from Crohn’s.
  • -Clin Gastro & Hepatology 2004; 2:xx. Dx of Peutz-Jeghers w WCE.
  • -Gastro 2004; 126: 643-653. WCE performs well for occult bleeding, especially active bleeding (87% detection rate)
  • -Clinical Gastro & Hepatology 2004; 2: 14-15, 31-40.
  • -Gastroenterology 2003; 124 (suppl 1) A37. abnl small bowel findings common in healthy subjects.
  • -JPGN 2003; 37: 332 (18A), n=58. Crohn’s, polyposis, occult bleeding
  • -Gastroenterology  2003; 124: suppl 1, A-37 (284) 22% of normal pts c abnl wireless findings
  • -Gastroenterology  2002; 123: 999-1005, 1385-88. capsule is superior to radiographs for suspected small bowel dz.
  • -Gastro Endosc 2002; 56: 452-456. Algorithm suggests using this modality if negative upper & lower endoscopy & no acute overt bleeding. If capsule endoscopy is negative & patient is stable, observation appropriate.
  • -Gastro Endosc 2002; 56: 621-24. ASGE guidelines.

Potential and pitfalls of probiotics with necrotizing enterocolitis

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Recent developments in necrotizing enterocolitis (NEC) have focused on the potential role of new biomarkers and preventive strategies (JPEN 2012; 36: 30S-35S).  In this report, the clinical/diagnostic features of NEC are reviewed:

  • classic form develops between 29-32 weeks corrected gestational age
  • features include feeding intolerance, abdominal distention, bloody stools
  • imaging features: pneumotosis intestinalis, portal venous gas, paucity of gas, fixed bowel loops
  • full term or late NEC usually occurs in the setting of risk factors like congenital heart disease, exchange transfusions, gastroschisis, and neural tube defects
  • spontaneous intestinal perforation due to glucocorticoids or indomethacin may be confused with NEC.  It usually occurs earlier than NEC

This review describes the potential for new biomarkers, including urinary I-FABP & fecal calprotectin. These assays would need to be available with very short turn-around time given the often rapid development of NEC.

Finally, this articles discusses the evidence for preventive measures.  Human milk has been shown to decrease NEC and gradual introduction of feedings remains important. With regard to microbial colonization, NEC does not occur until at least 8-10 days postpartum coincident with anerobic bacterial colonization of intestinal tract.

This has led to attempts to alter the colonization to decrease NEC incidence. 16 randomized controlled trials with 14 different probiotics have been completed.  Most are underpowered.  “The available trials do not permit a decision to be made with respect to optimum strain, dosing, or protocol.”  In a cautionary note, a preterm pig model demonstrated an increase NEC incidence with the use of a specific probiotic (Pediatr Res 2011; 69: 10-16).  Furthermore, probiotics are plagued by a lack of adequate quality control.

Additional references:

  • -Ann Surg 2010; 251: 1174-80.  Non-invasive biomarkers for NEC.
  • -J Peds 2011; 158: 672-74.  Caution advised with probiotics for NEC.
  • -J Peds 2011; 159: 392. n=124 cases (248 controls). retrospective study suggested that abx exposure is a risk factor for NEC (3-fold risk).  Abx -marker for illness or true predisposing factor?
  • -NEJM 2011; 364: 255-64.  NEC review.
  • -Cochrane Database Syst Rev 2011; 3: CD005496.  Probiotics for NEC.
  • -NEJM 2011; 364: 1877. Probiotics likely helpful in preemies with birth wt >1000gm.
  • -NEJM 2010; 364: 255.
  • -Pediatrics 2010; 125: 921-30.  Meta-analysis of probiotics for NEC.
  • -JPS 2009; 44: 1072-76. Mortalitiy of NEC expressed by birth weight.
  • –Pediatrics 2008; 122: 693-700. Multicenter trial of probiotics in VLBW for NEC prevention.
  • -J Pediatr 2008; 153: 339. Cluster of NEC due to norovirus.
  • -Pediatrics 2007; 119; e164. Rate of 0.4% among large cohort of infants w/o indocin, steroids & w slow delayed feedings.
  • -Pediatrics 2006; 117: e137. H2-blockers associated with increased NEC (?causal)
  • -Pediatrics 2005; 116: 1064. CRP helpful. If CRP was persistently normal, antibiotics were aborted and enteral feeds restarted safely.
  • -Pediatrics 2005; 115: 1-4 & 171 editorial.  Probiotics decreased NEC in this study.
  • -J Pediatr 2003; 143: 543. Images of pneumotosis.

Add it to the list

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A recent review article (NEJM 2012; 366: 158-64) describes a common, chronic recurrent granulomatous inflammatory disease that manifests as painful, deep-seated inflamed lesions (including sinus tracts and abscesses); it typically starts after puberty.  This disease is due in part to aberrant healing processes and impaired mechanical integrity. Investigations have shown that tumor necrosis factor α is involved in the pathogenesis of hidradenitis suppurativa.  There are a lot of similarities between hidradenitis suppurativa and Crohn’s disease as well as some overlap as up to 17% of individuals with Crohn’s disease have hidradenitis suppurativa.  In addition, hidradenitis suppurativa can be confused with Crohn’s disease especially when buttocks/perianal lesions are present.

Key clinical points with this disease:

  • Affects skin with apocrine glands
  • Long delay in diagnosis is common though disorder may affect 1% of population
  • Incision and drainage is not effective treatment –lesions recur
  • Few randomized studies –most often treated with combination of antibiotics (eg. clindamycin & rifampin)
  • More severe disease may benefit from TNF inhibitors or possibly complete surgical excision
For pediatric gastroenterologists, hidradenitis suppurative is another to add to the Crohn’s differential diagnosis list:
 

Infectious etiologies: 

Histoplasma , Amebiasis, CMV, C. diff, Klebsiella oxytoca, Actinomycosis, HIV

Noninfectious etiologies:

Sarcoidosis, Vasculitis (HSP,dermatomyositis, Wegener’s, SLE), FMF, allergic colitis, Hirschsprung’s, autoimmune enteropathy, Chronic granulomatous disease, glycogen storage dz, 1B, Hermansky-Pudlak syndrome, Wiskott Aldrich syndrome, NEMO (NF-kB essential modifier) deficiency, Leukocyte adhesion deficiency, SCID, Behcet’s, FELS/hemophagocytic lymphohistiocytosis, Typhlitis

Additional reference for hidradenitis suppurativa:

  • -Br J Dermatol 2010; 162: 195-7.

Crohn’s Disease and differential diagnosis -references:

  • -JPGN 2010; 51: 690. Discusses sarcoid (check angiotensin converting enzyme), CGD, Hermansky Pudlak
  • -JPGN 2010; 50: 99. Perianal dz in young children may be due to autoimmune neutropenia.
  • -IBD 2008; 14: 1443. Phagocyte dysfunction. Also, discusses Hermansky-Pudlak, GSD 1B, chronic granulomatous disease, Chediak-Higashi, leukocyte adhesion deficiency, cylic neutropenia, congenital neutropenia
  • -JPGN 2006; 42: 405. Vasculitis mimicking IBD.
  • -NEJM 2005; 352: 489-94.
  • -J Clin Gastroenterol 1992; 15: 17-23.
  • -NEJM 2003; 349 (26): 2541-49.  Table 2. (Gold et al.)

When nothing else is working

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The situation when “nothing else is working” comes up with a number of pediatric gastroenterology phenotypes, including inflammatory bowel disease, encopresis, and functional abdominal pain.  With severe refractory Crohn’s disease, the use of Thalidomide has been explored (JPGN 2012; 54: 28-33).  In this recent description of 12 refractory patients (three females), followed over an average of 4.6 years, thalidomide was associated with improvement in many outcome measures.  All patients were refractory to multiple other medical therapies (particularly infliximab and adalimumab).  Five of seven patients with fistulas had complete resolution, Harvey-Bradshaw index improved (11.8–>3.9), steroid dependency improved (daily dose 13.9–>2.3mg/day), sedimentation rate improved (35–>14), and both hospitalizations & surgeries decreased.

However, 42% developed peripheral neuropathy and adverse reactions resulted in discontinuation in nine of the patients.  The peripheral neuropathy developed on average 43 months into treatment (range 12-79 months) and clinically resolved in all patients within 2-3 months after discontinuation.  All patients enrolled participated in close monitoring as required by the FDA STEPS program —system of thalidomide education and prescribing safety.

Additional references:

  • -JPGN 2003; 37: 522, UK experience. 4/6 developed peripheral neuropathy.
  • -J Pediatr 2004; 145: 856. use for JRA
  • -JPGN 2001; 32: 322-25. Irreversible neuropathy noted in patient after 9 months of Rx.
  • -JPGN 1999; 28: 214.  Response w/in one month
  • -Pediatrics 1999; 103: 1295. (in Behcet’s)
  • -Gastroenterology 1999; 117: 1271 & 1278.  22 men c refractory Crohn’s, dosed @ 200mg qhs: 9 clinical remission & 16 c response. 12 steroid-dependent men @50 or 100mg qhs: 44% off steroids over 12 weeks.
  • -JPGN 2000; 31 (supp 2) A611. Dose 1.5-2mg/kg/day in 5 males.

Eat your veggies…if you don’t want to get sick

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Maybe your mother was right –you should eat your vegetables!   For a long time, it has been known that dietary changes can be used to treat Crohn’s disease.  The specifics about what type of diet and the reasons for how diet promotes a healthy gastrointestinal tract are being unraveled.  A person’s diet affects their microbiome; and, a number of recent articles have highlighted the microbiome in both functional and nonfunctional disorders (see below).

An even more fascinating article is in last week’s New England Journal of Medicine (NEJM 2012; 366: 181).  This article discusses two publications which show how certain dietary components interact with intestinal immune receptors.

  • Kiss EA et al. Science 2011 October 27 (Epub ahead of print).
  • Li Y et al. Cell 2011; 147: 629-40.

This NEJM article implicates a typical ‘Western’ diet as a contributor to inflammatory bowel disease (IBD).  However, a diet high in vegetables may prevent or reduce inflammation.  One mechanism whereby vegetables affect the GI tract is through the AhR (aryl hydrocarbon) receptor.  Some vegetables, like broccoli, cabbage, and brussel sprouts, are natural ligands for this receptor.  A mouse model has shown that AhR deficiency “results in increased epithelial vulnerability, immune activation, and altered composition of the microbiota.”  In addition, AhR is down-regulated in the intestinal tissue of persons with IBD.  AhR ligands are associated with increased interleukin-22 which promotes intestinal integrity.

Additional work regarding the optimal diet are ongoing.  There has been an interest in a ‘carbohydrate specific diet.’  This year’s NASPGHAN meeting (abstract #48)  presented data on this diet from a retrospective study.  This poster described five patients on monotherapy (diet alone) and at 6 months –good results in four patients (80%).  A few prospective studies are underway; in fact, a prospective study with patients from our office will be presented at this year’s DDW.  Initial results look promising (personal communication from lead investigator, Stan Cohen).

Additional references:

  • -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.
  • -Gastro 2011; 141: 28, 208.  GM-CSF receptor (CD116) defective expression & function in 85% of IBD pts. n=52.
  • -Scand J Gastro 2001; 36: 383-8.  Elemental & polymeric diets successful in maintaining remission in ~43% of adults with complete steroid withdrawal.
  • -Clin Gastro & Hepatology 2006; 4: 744.  10 weeks of exclusive modulen (along with clears) had 79% response rate (n=37).  Better histologic response than steroids.
  • -J Pediatr 2000; 136: 285. Nutritional treatment w polymeric diet is effective w/in 8 weeks in 32/37.
  • -JPGN 2000; 31: 3 & 8.  EN about as effective as steroids for primary Rx.
  • -Can J Gastroenterol 1998; 12(8):544-49. Patients, diets and preferences in
    a pediatric population with Crohn’s disease.
  • -Gastroenterology 1988; 94:603-610. Chronic intermittent elemental diet improves growth failure in  children with Crohn’s disease.
  • -JPGN 1989; 8:8-12. Nutritional support for pediatric patients with inflammatory bowel disease.
  • -J Pediatr 2000; 136: 285-91. The role of nutrition in treating pediatric Crohn’s disease in the new millennium.

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.