Category Archives: Pediatric Gastroenterology Intestinal Disorder

Magnetic resonance enterography for Crohn’s disease

Posted on by

Magnetic resonance enterography (MRE) has increasingly been recognized as an effective way to characterize small bowel disease in Crohn’s disease (Inflamm Bowel Dis 2012; 18: 520-28).

In this retrospective pediatric study, 95 patients with Crohn’s disease underwent MRE from 2006-2009.  As expected, terminal ileal disease was the most common site of involvement with 54%; this was followed by ileum with 19%, and jejunum with 17%.  Other findings included solitary jejunal inflammation (3.7%), small bowel stenosis (1.9%) fistula (1%), and abscess (1%).  Specific evidence of inflammation included contrast enhancement, bowel wall thickening or derangement of bowel wall shape.  The images in the article are excellent.

The main advantage of MRE over CT enterography (CTE) is the lack of ionizing radiation.  In addition, MRE can better detect soft tissue contrast suggestive of bowel wall edema.  This helps distinguish acute from chronic inflammation.  Obtaining an MRE is technically more challenging and more costly.  The youngest patient in the study was seven; though the authors note that the youngest patient they have performed MRE was six.

Additional references:

  • More imaging needed?
  • -JPGN 2010; 51: 603.  MRE for suspected IBD.  Useful in pediatric Crohn’s disease.
  • -IBD 2009; 15: 1635. U/S compared favorably with endoscopy in correlating postoperative recurrence with Crohn’s.
  • -Clin Gastro Hepatol 2006; 3: 1221. MRI as accurate in evaluating ileocolonic disease with flareups as endoscopy.
  • -IBD 2004; 10: 452-61. U/S was very helpful in identifying disease and complications.

Drug levels for inflammatory bowel disease

Posted on by

In many conditions, drug levels are helpful to make sure the patient receives an adequate dose for the indication.  When we treat infections or seizures, drug levels predict the effectiveness of the medication and allow dosing adjustments to improve responses as well as to lower toxicity. Drug levels are helpful in inflammatory bowel disease (IBD) as well.  Drug levels may help with thiopurine dosing and with infliximab (IFX) dosing.

Infliximab (IFX) levels can guide therapy (Scand J Gastroeneterol 2011; 46: 310-18). This study examined 106 patients (85 with CD and 21 with UC) over a ten-year period. In this cohort, patients received concurrent hydrocortisone, acetaminophen, and cetirizine to prevent acute reactions and to try to limit anti-infliximab antibodies (ATI), also called anti-human antichimeric antibodies (HACA).  Infusion intervals ranged from 4-12 weeks.

69% of Crohn’s patients maintained response to IFX and 48% of UC patients.  Infliximab trough levels were significantly increased among patients who maintained their response.  A cutoff value of 0.5 μg/mL was defined as clinically relevant for IFX trough concentrations for Crohn’s patients and for UC the cutoff was 0.8 μg/mL .  Trough levels below this cutoff were 86% sensitive and 85% specific for identifying loss of response.  The overall accuracy for the test was 87% in identifying loss of response.

Also, ATIs were significantly higher in CD patients who had lost response to infliximab.  Patients who had been “re-treated,” were significantly more likely to have developed ATIs.  “Re-treated” was defined as having interruption of IFX treatment more than 6 months.

These specific cutoff values apply to the radioimmunoassay technique for measuring IFX and ATI.  These values may not extrapolate to ELISA assays.  At the same time, the findings suggest a practical approach in patients with symptoms while receiving IFX:

  • Check IFX level (at trough or at 4 weeks)
  • If low level and no ATI, likely to respond to dose escalation
  • If low level but positive for ATI, not likely to respond to dose escalation
  • Do not assume symptoms are due to drug failure; reassess with imaging &/or scope. Consider alternate etiologies (eg infections, stricture, celiac, IBS).
  • Cotherapy with an immunomodulator reduces ATIs and boosts levels of IFX.
More usage of IFX and ATI levels is likely; however, cost issues preclude frequent measurements.

Additional references:

  • Only one chance to make first impression.  Previous blog entry on use of infliximab.
  • -Clin Gastro & Hepatology 2011; 9: 395. Do not assume symptoms are due to drug failure -reassess with imaging &/or scope. Consider alternate etiologies (eg infections, stricture, celiac, IBS). Check IFX level –if >12 @ 4weeks or >1.4 mcg/mL at trough –>predicts good response.  If +HACA, ~90% response with alternative TNF.  In those with low level, 86% responded to dose escalation.
  • -DDW 2011, Abstract #772. If loss of response to IFX, **confirm active dz (labs, scope) & not due to CDT. **check HACA –if +, only 10-20% chance of responding to dose escalation; better chance of responding to similar agent **check IFX week 4 level, if low (& neg HACA) then 90% respond to dose escalation
  • -NEJM 2010; 362:1383-1395. SONIC study.  Patients with moderate-to-severe Crohn’s disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy.
  • -Gut 2010; 59: 49-54. Trough IFX levels in UC. n=115. Antibody status can only be measured at trough levels. Undetectable trough level (<1.4 mcg/mL) associated with lower remission (15% vs 69%) and lower endoscopic response (28% vs 76%) & higher colectomy rate (55% vs. 7%).
  • -Gastroenterology 2010; 139: 344 (review of above Gut article). Similar to Crohn’s disease: 82% remission with detectable trough vs 6% w/o detectable level.
  • –Lancet 354 (9194): 1932–9. doi:10.1016/S0140-6736(99)05246-0. PMID 10622295.”Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group”.
  • -Am J Gastroenterol 2010; 105: 1133-39. If lack/loss of response, may need dose escalation with humira or Cimzia (q2weeks):
  • -IBD 2011; 17: 141-51. Loss of response to biologics.
  • -Gastro & Hep 2008; 4: 12. “primary nonresponse can be determined after 2 doses” in table reiterating AGA consensus guidelines. 85% of responders show benefit by 2weeks & all responders benefit c/in 6 weeks (Am J Gastro 2001; 96: S303). Worsening Sx despite infliximab indicates need to look for stricture, infxn, etc.
  • -Clin Gastro & Hep 2006; 4: 1248. Clinical remission associated with measurable infliximab troughs; thus, if no measurable trough, increase dose or shorten interval. If level detected & no response, unlikely to respnd to TNF class. Also, concurrent immunomodulators were not helpful.
  • -Am J Gastro 2010; 105: 2617 (Oussalah et al). 2-3yrs 41% IFX failure in UC. withdrawal of AZA increase loss of response –7x more likely
  • -Am J Gastro ; 105: 1133-40. n=155. 23% ATI -92% respond to med change, 17% respond to dose change. Level <12 @ 4weeks, 86% respond to dose change
  • -Gut 2010; 59: 1363. n=121. Co-treatment helped reduce complications & flares relative to monotherapy (& azathioprine appeared to be more effective than methotrexate).

Vitamin D, IBD, and Causality

Posted on by

The importance of vitamin D has been noted in this blog previously (Common to be “D-ficient” ).  Now a study implicates vitamin D as a risk factor for developing inflammatory bowel disease, especially for Crohn’s disease (Gastroenterology 2012: 142: 482-89).  It is known that vitamin D influences innate immunity.  As such, it may play a role in the susceptibility to Crohn’s disease (CD) and Ulcerative colitis (UC).

This prospective study included 72,719 women (age 40-73) enrolled in the Nurses’ Health Study.  Research subjects completed an assessment of diet and lifestyle along with 25-hydroxy vitamin D [25(OH)D] levels.  The 25(OH)D levels were predicted; this prediction was based on a validated model which included vitamin D intake, sun exposure, race, and body mass index (J Natl Cancer Inst 2006; 98: 451-9).  This model was validated against directly measured 25(OH)D levels.

During nearly 1.5 million person-years of followup, 122 incident cases of CD and 123 cases of UC occurred.  The adjusted hazard ratio (HR) for the highest quartile of 25(OH)D was 0.54 for CD and 0.65 for UC compared to the lowest quartile.  Compared with a level less than 20, the highest quartile HR was 0.38 for CD and 0.57 for UC.

In addition, the authors identified a significant inverse association between dietary supplemental vitamin D and UC; an insignificant reduction in CD risk was noted with dietary intake.  Although it is difficult to determine causality, these data convincingly show that ‘healthy’ levels of vitamin D are associated with a lower risk of IBD.

Proven treatments for mitochondrial disorders

Posted on by

The title is misleading; the most frequent treatments are unproven and not tailored well to the numerous disorders lumped under the term ‘mitochondrial disease.’  A nice review on what’s up-to-date with ‘mito’ disorders is in a recent NEJM (NEJM 2012; 366; 1132-41).

The first part of the review details the structure and function of the mitochondria including those pesky pathways for the production of ATP: glucose –>pyruvate through glycolysis.  In turn, pyruvate –>lactate –>acetyl coenzyme A (CoA).  Acetyl CoA generates NADH & flavin via tricarboxylic acid cycle.  Fatty acids and glutamine can also serve as substrates.  NADH & FADH2 fuel oxidative phosphorylation through five coupled mitochondria protein complexes.  Coenzyme Q10 helps transport electrons across the complexes.

Primary and secondary mitochodrial disorders.

  • 1000 genes encoding mitochondrial proteins have been identified in humans
  • 228 mutations of protein-encoding nuclear DNA (nDNA) and 13 mitoDNA (mtDNA) have been linked to human disorders
  • Secondary mito disorders include mito dysfunction due to viral infections and ‘off-target’ drug effects.  Specific drugs include valproic acid, statins, halothane, doxorubicin, and aspirin
  • Mito dysfunction is seen in a number of other diseases including Alzheimer’s, Parkinson’s, cancers, cardiac disease, diabetes, and obesity

Diagnosis:  Biopsy specimens from patients can be studied to assess cellular and mitochondrial physiology in comparison to healthy samples.  This review does not discuss molecular testing for mutations; however, an extensive list of genes associated with mitochondrial disorders (mtDNA & nDNA) is listed in Figure 2; a supplementary online appendix to the article explains these mutations in more depth.

Four potential treatments –all with a goal of increasing ATP production:

  • genetic therapy
  • small molecule treatment
  • metabolic manipulation
  • diet/exercise

Previous Cochrane review (2006) has not found evidence to support the use of any therapeutic interventions.  More recent trials have shown limited positive effects on clinical or biochemical end points but have not led to a New Drug Application with the FDA.  A few specific disorders that have treatments include the following:

  • Idebenone (a CoQ10 variant) for Friedreich’s ataxia & Leber’s hereditary optic neuropathy
  • Ketogenic diet for improving seizures in children with electron-transport defects
  • Cyclosporin A for secondary mito dysfunction in Ulrich’s congenital muscular dystrophy & Bethlem’s myopathy
  • Overview of current trials: http://www.clinicaltrials.gov/ct2/results?term-mitochondrial+disease

As one of my colleagues (LS) has said, making a diagnosis of a mitochondrial disorder is like getting the license plate of the bus that ran you over.  Until treatments improve, this is pretty much the case.

Additional reference:

  • -Mitochondrion 2011; 11: 679-85. Why are there no proven therapies for genetic mitochondrial diseases?
  • -J Pediatr 2011; 158: 802.  Developing liver toxicity with VPA is a contraindication to OLTx (even in the absence of documented mitochondrial dz).  Rx with carnitine and d/c VPA.  82% of 17 children died w/in 1 yr of OLTx.  POLG1 mutations are associated with Alpers syndrome.
  • -Pediatrics 2007; 120: 1326. Diagnosis and complications of mitochondrial disease.
  • -Pediatrics 2007; 119: 722. long-term outcome of mito dz –variable.
  • -NEJM 2003; 348: 2656. Review

Ivacaftor for Cystic Fibrosis

Posted on by

Recent FDA approval of Ivacaftor (Kalydeco) is a promising step for a subset of patients with cystic fibrosis who have the G551D mutation.  This drug enhances the cystic fibrosis transmembrane regulator (CFTR) gene in these patients; only ~4% of CF patients or about 1200 patients in the US have this genetic defect.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm

Additional references:

-NEJM 2011; 365: 1663. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 167 pts. (Ivacaftor).
-NEJM 2010; 363: 1991. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 39 adults.

Treating reflux does not help asthma

Posted on by

Studies in adults have looked at the use of PPIs for asthma and have not shown improvement (see references below).  Now a trial of lansoprazole suggests the same is true in children (JAMA 2012; 307: 373-81).  This study was a randomized double-blind placebo-controlled study of 306 children with a mean age of 11; the participants were recruited from 19 academic medical centers in the US.  149 children received lansoprazole and 157 received placebo.  The dose of lansoprazole was 15mg in patients weighing less than 30kg, and 30mg in those weighing more than 30kg.

Those treated with lansoprazole did no better than placebo with regard to symptoms and lung function.  The main outcome was the asthma control questionnaire (ACQ) score. The lansoprazole group had a mean change in this score of 0.2 units which was not a meaningful change. More precise measures of lung function including forced expiratory volume also did not differ.

In a subgroup of 115 patients who had esophageal pH studies, the prevalence of GER was 43%.  Yet, no treatment effect for lansoprazole was observed for any asthma outcome.

Not only did lansoprazole not help, the treatment group experienced more adverse effects, including respiratory infections (relative risk 1.3), sore throats (RR 1.3), and episodes of bronchitis (RR 2.2).  Though not statistically significant, the treatment group had more activity-related fractures, six compared to one in the placebo group.

This study took several years to complete (2007-2010).  I congratulate the authors, especially the third author Benjamin Gold, for this excellent work.

http://www.ccdhc.org/doctors/gold.html

Additional references:

The Medical Pendulum and Gastroesophageal Reflux

GERD and respiratory/ENT issues:

  • –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.
  • –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.

All bleeding stops

Posted on by

Although the title is technically true, there are preferred ways to stop GI bleeding (Clinical Gastroenterol & Hepatol 2012; 10: 234-39).  This article summarizes the approach for nonvariceal upper GI bleeding.

Recommendations:

  • Endoscopy within 24 hours following ABCs/adequate resuscitation.  Use of a promotility agent prior to endoscopy may be helpful (in pediatric patients: erythromycin ~3 mg/kg)
  • Correct coagulopathy but do not delay endoscopy.
  • Consider nasogastric tube placement.
  • Do not use somatostatin or octreotide.
  • High-risk endoscopic stigmata should receive endoscopic hemostasis.  These lesions include actively spurting, oozing blood, nonbleeding visible vessel, and an adherent clot.
  • Pigmented dots or clean base ulcers do not require endoscopic hemostasis.
  • Endoscopic management includes clips, thermocoagulation, or sclerosant injection alone or in combination with epinephrine injection.  Epinephrine alone is not recommended for high risk lesions.
  • If a clot is found, attempts to remove it should be made to visualize underlying lesion.  If clot is adherent, intensive IV PPI therapy may be sufficient.  A typical dose would be esomeprazole 80mg bolus (for an adult) followed by 8 mg/hour for 72 hours.
  • Stable patients can be fed within 24 hours.
• IV PPI dose: 1mg/kg bolus followed by 0.1mg/kg/hr infusion.

Additional references:

  • -Ann Intern Med 2010; 152: 101-113. Consensus recommendations on UGI bleeding. Early endoscopy (<24hrs), data support attempts to dislodge clots, consider clips or thermocoagulation for Rx. Preendosocpy PPI can be helpful.
  • -Clin Gastro & Hep 2010; 8: 651. Article suggests second look only if difficult visualization on initial endoscopy (eg unable to remove clot).
  • -Ann Intern Med 2010; 152: 101-13. Systematic review of on UGI bleeding. Use IV PPI bolus, then continuous PPI if high risk stigmata after endoscopic Rx. Hospitalize for at least 72hrs.
  • -Gastroenterology 2010; 138: 1252. Review of upper GI bleeding.
  • -Clin Gastro & Hep 2009; 7: 828. Review of recurrent GI bleeding with negative initial evaluation.
  • -Gastroenterology 2008; 134: 1836. Frequent high dose oral PPI also effective with bleeding ulcers: prevacid 120mg x1, then 30mg q3hrs compared favorably with 90mg IV followed by 9mg/hr. n=66. intragastric pH >6 for 68% of study in IV PPI vs. 65% in oral PPI. 1st hour -more rapid onset with IV PPI.
  • -Gastroenterology 2007; 133: 1694. Position statement & review on obscure bleeding.
  • -Ann Intern Med 2003; 139: 843-857. Consensus on nonvariceal bleeding. Rec: lansoprazole 90mg bolus, then 6mg/hr x 72hrs or pantoprazole 80mg then 8mg/hr in high risk lesions
  • -Clin Gastro & Hep 2006; 4: 1459. Trends in non-variceal bleeding between 1993-2003 do NOT show improved outcomes with PPI. Overall mortality fairly steady @3.5%
  • -Clin Gastro & Hep 2005; 3: 959. WCE should be 2nd step in obscure bleed, p egd/col.
  • -NEJM 2004; 351: 488. case review.
  • -Gastroenterology 2002; 123: 17-23. IV erythromycin, 20 minutes before endoscopy, helped clear stomach (82% clear vs. 33% c placebo). Adults in this study received 250 mg. (thus, children probably need 3-4 mg/kg)
  • -Gastro Endosc 2002; 56: 174. erythromycin helpful-3mg/kg IV over 30 min
  • -Gastroenterology 2002; 123: 407-13. Endoscopic Rx of adherent clots c PUDz helpful (epinephrine injection, cold guillotining of clot, then coagulation cautery); Editorial on 632-635 emphasizes vigourous washing BUT NOT to remove adherent clot unless in centers with low rebleeding rates. Additionally, PPIs very helpful in preventing rebleeding in this situation (NEJM 1997; 336: 1054-8).
  • -NEJM 1999; 341: 38. Occult bleeding
  • -Gastroenterology 2000; 118: 197. AGA position statement.
  • -Gastro Endosc 2001; 53: 853 & 859. ASGE guidelines/algorithm for upper & lower GI bleeding

Gluten sensitivity without celiac disease

Posted on by

Gluten free is big business.  In a range of conditions, eliminating gluten has been advocated to improve symptoms.  The most frequent problem in which a gluten-free diet (GFD) may be beneficial is irritable bowel syndrome (IBS).  A selected summary in Gastroenterology discusses this topic (Gastroenterology 2012; 142: 664-73).

This review highlights an article that showed improvement in a double-blind randomized trial (Am J Gastroenterol 2011; 106: 508-14) & then reviews the topic more broadly.  The study is the first randomized controlled trial that suggests that nonceliac IBS patients may improve with a GFD.  The study looked at 34 patients with IBS who had improved with a GFD & had no evidence of celiac disease (either negative HLA-DQ2/DQ8 or duodenal biopsy).  Then 19 patients had 16g of gluten per day reintroduced; control patients were offered equivalent food that was gluten-free.  The gluten products in the study were free of fermentable oligo-, di-, monosaccharides and polyols to avoid confounders (What to make of FODMAPs).  The patients who continued a GFD had less reported pain, bloating and tiredness.  The GFD group reported good control of symptoms the previous week in 68% vs. 40% in the study group.

The commentary notes that ‘gluten sensitivity’ is big business, accounting for 1.3 billion in 2011 expenditures.  Companies like General Mills, Betty Crocker, PF Chang’s, and Subway are offering gluten-free choices.  Since immune activation and low-grade inflammation may be important for IBS, it is possible that some foods trigger these processes.  At the same time, individuals with reported gluten sensitivity have not been shown to have increased intestinal permeability; this is in contrast to celiac disease (BMC Med 2011; 9; 23).

There may be more patients with IBS who will benefit from a GFD due to gluten sensitivity than patients with celiac disease.

Additional references:

  • -Nutr Clin Pract. 2011;26:294-299.  A gluten-free diet (GFD) is commonly recognized as the treatment for celiac disease. It also has been investigated as a treatment option for other medical conditions, including dermatitis herpetiformis, irritable bowel syndrome, neurologic disorders, rheumatoid arthritis, diabetes mellitus, and HIV-associated enteropathy. The strength of the evidence for the use of a GFD in these nonceliac diseases varies.
  • -Clin Gastro & Hep 2007; 5: 844. GFD in IBS pts (w/o celiac)
  • -Am J Gastro 2009; 104: 1587. Gluten sensitivity in IBS (w celiac)
  • -Gastroenterology 2011; 141: 1187. Prevalence of celiac similar in IBS as general population though higher number (7%) with celiac antibodies (esp gliadin).
  • -Am J Gastro 2008; 103: S472 (abstract P687) Serology for Celiac in IBS patients same as in controls. n=566. n=555 controls.
  • -Clin Gastro & Hep 2007; 5: 844. d-IBS patients may respond to gluten-free diet, especially if positive HLA-DQ2 expression or positive celiac serology.
  • -Lancet 2001; 358: 1504-08. n=300 uninvestigated pts w IBS criteria & 300 controls. 66 w positive serology; 14 w biopsy-proven celiac dz, 43 w normal biopsies. Odds ratio of 7 to have celiac compared to control group (2 w biopsy-proven disease).

Is a biopsy necessary in Celiac disease?

Posted on by

Yes, at least for now.  That is the conclusion of a recent editorial (JPGN 2012; 54: 310-11) regarding Kurpa et al (JPGN 2012; 54: 387-91).  The article by Kurpa et al discusses the utility of the ESPGHAN criteria for diagnosis of celiac disease.  Among the patients with strongly positive TTG (> 100 units), 94% had a diagnosis of Celiac disease confirmed with biopsy; in addition, this result correlated well with positive endomysial antibody and with positive DQ2/8. In those with TTG (30-99 units), Celiac disease was diagnosed in 69% of children and 86% of adults.

Additional references:

  • -JPGN 2011;52: 554. May not need to biopsy if TTG >100 & responds to GFD
  • -Clin Gastro & Hep 2011; 9: 320. Nat’l hx in children with +serology. n=106. 33% developed villous atrophy c/in 2 yrs.
  • -Gastroenterology 2010; 139: 763. Mortality NOT worsened in undiagnosed celiac dz in Olmstead County, though bone density decreased. n=129 of 16,847. (?milder cases undiagnosed)
  • -J Pediatr 2010; 157: 373, 353. Even pts w/o villous atrophy & +serology, benefited from GFD with regard to GI symptoms and serological markers.
  • -JPGN 2010; 50: 397. n=250. +association
  • -Mohamed BM, et al. The Absence of a Mucosal Lesion on Standard Histological Examination Does Not Exclude Diagnosis of Celiac Disease.  Dig Dis Sci. 2007 May 9;
  • -JPGN 2009; 49: 52. deamidated gliadin -new, accurate biomarker for celiac. n=302.
  • -Gastroenterology 2009; 137: 88. Increased mortality in undiagnosed celiac –4-fold increase. Also, increasing prevalence ~4 fold in last 50 yrs.
  • -Gastroenterology 1967; 52: 893-897. Seminal article ‘gluten as culprit in celiac’
  • -Gastroenterology 2009; 136: 816. Mild enteropathy w Celiac –still needs GFD
  • -JPGN 2008; 47: 618. duodenal bulb always abnl, n=665
  • -Clin Gastro & Hep 2008; 6: 753. Incidence of autoimmune diseases less in those compliant with diet. n=178.
  • -Clinical Gastro & Hep 2008; 6: 426. Usefulness of deamidated gliadin antibodies (about as useful as TTG). In this study with n=216 celiac pts and 124 controls, TTG had sensitivity of 78% and 98% specificity.
  • -JPGN 2007; 45: 497. ~1% of UK kids c celiac; 90% missed. Avon study (ALSPAC). n=5470 screened from cohort of 13,971
  • -NEJM 2007; 357: 1731. Nice review which suggests the introduction of gluten 4-7 months in healthy infants. HLA DQ2 present in 90-95%; HLA DQ8 in remainder. Both also present in gen population, 30-40%. Scalloping of mucosal folds often seen. Can stain bx for CD3, CD8 receptors. More refractory cases stain only for CD3 (neg for CD8).

Stimulants for constipation

Posted on by

Overall, 12-19% of Americans are affected by chronic constipation (Am J Gastroenterol 2004; 9: 750-59).  Despite the fact that constipation problems are widespread, the amount of useful research available to guide treatment is quite limited.  Two recent articles do offer some information:

  • Clin Gastroenterol Hepatol 2011; 9: 577-83.
  • Gut 2011; 60: 209-18.

The first reference examined the use of bisacodyl in a randomized, double-blind placebo-controlled study in the UK.  During the 4-week treatment period, patients receiving 10mg/day bisacodyl (n=247) had increased stools, from 1.1 per week to 5.2 per week.  Stool frequency also increased to 1.9 per week in the placebo group (n=121).  All secondary endpoints including constipation-associated symptoms (eg. quality of life indices, physical discomfort) improved significantly compared to placebo.  Average age of patients in this study was 55 years.  The main adverse effect was diarrhea –mainly during the 1st week of therapy.

A selected summary in Gastroenterology (Gastroenterology 2012; 142: 402-404) reviews the first study and makes several useful points:

  • Stimulant laxative use has been hindered by myths & misconceptions along with lack of supporting data.  Most recent studies do not support a role of stimulant use in causing enteric neuropathies, a cathartic colon or increasing the risk of colon cancer
  • Osmotic laxatives have been favored in guidelines but this has not been bolstered by supporting data
  • Only recently have two large randomized controlled studies proven the efficacy and safety of stimulant laxatives over the short-term
  • Long-term prospective studies are not available on the use of stimulant laxatives.

The second reference is a systematic review and meta-analysis of randomized controlled trials (RCTs) of pharmacologic therapy for chronic idiopathic constipation.  Twenty one eligible RCTs were identified: eight laxative studies (n=1411), seven prucalopride studies (n=2639), three lubiprostone (n=610), and three linactolide trials (n=1582).  All of these studies showed treatment was superior to placebo. These studies involved subjects who were mainly adults (>90% older than 16 years).

The results showed benefit from both stimulant and osmotic laxatives.  Overall, the osmotic and stimulant laxative studies showed higher response than the pharmacologic agents like prucalopride, lubiprostone, and linaclotide.  Nevertheless, between 50% and 85% of patients did not fulfill criteria for response to therapy.

Additional references:

  • -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”
  • -J Pediatr 2009; 154: 258.  Constipation associated w 3-fold increase in health utilization/cost.
  • -Clin Gastro  Hep 2009; 7: 20.  Review of complications assoc c constipation in adults.
  • -Pediatrics 2008; 121: e1334.  Behavioral therapy ineffective in treating childhood constipation.
  • -NEJM 2008; 358: 2332, 2344.  Use of methylnatrexone for opioid-induced constipation & trial of n=620 of prucalopride for severe constipation.  Both drugs were helpful.
  • -Gastroenterology 2004; 126: S33. Review of pediatric incontinence.
  • -J Pediatr 2004; 145: 253-4.  Prevalence of encopresis 15% /constipation 23% in obese children  (n=80).  Questionnaire administered to 80 consecutive obese children.
  • -Gastroenterology 2003; 125: 357.  Longterm constipation followup.  one-third with 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