Category Archives: Pediatric Gastroenterology Intestinal Disorder

Is There a Link Between Maternal Iron Supplementation and Celiac Disease?

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According to a recent study, maternal iron supplementation may increase the risk of celiac disease in children (Clin Gastroenterol Hepatol 2014; 12: 624-31).

Using the Norwegian Mother and Child cohort study (1999-2008) which included data for 78,846 children, the authors analyzed the risk of developing celiac disease by examining prospectively collected questionnaires regarding iron supplements, diet, and anemia.  Questionnaires were obtained 3 times during pregnancy, then at age 18 months, 6 years, 7 years and 8 years.

Key Results:

  • 4.65 of 1000 children whose mothers took iron supplements while pregnant developed celiac disease compared to 3.15 of 1000 whose mothers did not.
  • After adjustment for multiple variables, the OR was 1.33 for children developing celiac disease if their mother took iron supplementation during pregnancy.
  • The authors note that maternal anemia was not associated with celiac disease in offspring nor was iron supplementation in childhood.

While these findings are intriguing, the associated editorial (pg 632-35) notes that unmeasured confounding variables could explain the findings.  For example, undiagnosed maternal celiac disease which could increase the likelihood of iron exposure could increase the risk of celiac disease in the offspring and account for the increased association with iron supplementation.

Take-home message (from the editorial): “it is premature to argue that iron supplementation during pregnancy should be avoided in individuals with celiac disease…the observed effect (an absolute risk increase of 0.15%) is modest in magnitude. This exposure is not driving the slow, ongoing epidemic of celiac disease.”

Related blog links:

Head-to-Head: Capsule Endoscopy versus Colonoscopy

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A recent study shows how useful capsule endoscopy (CE) can be in diagnosing Crohn disease (Clin Gastroenterol Hepatol 2014; 12: 609-15).  Congratulations to one of my partners, Dr. Stan Cohen, who is one of the authors.

This prospective study examined 80 patients with signs and/or symptoms of small-bowel Crohn disease (age, 10-65 years) who underwent CE, small-bowel follow-through (SBFT), and colonoscopy.

Presenting suggestive features included the following:

  • Diarrhea >6 weeks but less than 3 years
  • Abdominal pain >6 weeks but less than 3 years
  • Extraintestinal IBD manifestations: pyoderma gangrenosum, erythema nodosum, perianal disease, arthritis, aphthous stomatitis, and uveitis
  • Along with abnormal laboratory/clinical finding:
  1. positive inflammatory marker: sedimentation rate, C-reactive protein, calprotectin/lactoferrin
  2. unexplained iron deficiency
  3. hypoalbuminemia
  4. positive IBD serology (eg. anti-Saccharomyces cerevisiae antibodies)
  5. or other clinical findings: recurrent fevers, GI bleeding, growth failure, abnormal radiologic study

Results:

  • CE/colonoscopy in combination detected 107 of 110 inflammatory lesions (97.3%)
  • SBFT/colonoscopy detected 63 lesions (57.3%)
  • “The diagnostic yield of CE compared with colonoscopy was not different.”
  • Of the 80 patients with suspected Crohn disease, 25 (31.3%) had the diagnosis confirmed. 9 patients had diagnostic findings on at least 2 of the 3 modalities.  11 were diagnosed with CE alone and 5 by colonoscopy alone.

The authors conclude that colonoscopy remains the initial diagnostic test of choice.  However, “CE is safe and can establish the diagnosis of Crohn’s disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated.”

Take-home message: in patients with symptoms suggestive of Crohn disease, a negative colonoscopy is not sufficient to exclude the disease.  Other modalities like CE or MRE may be needed.

Related post:

Pediatric Capsule Endoscopy Experience

Macrolide Antibiotics and Pyloric Stenosis

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It is well-recognized that infants who receive macrolide antibiotics are at increased risk of pyloric stenosis. A recent study (BMJ 2014;348:g1908) indicates that maternal macrolide intake can also increase the risk of pyloric stenosis in their infants.

Link to article from NASPGHAN twitter feed: http://t.co/CnkbdZoRVf

Conclusions Treatment of young infants with macrolide antibiotics was strongly associated with IHPS and should therefore only be administered if potential treatment benefits outweigh the risk. Maternal use of macrolides during the first two weeks after birth was also associated with an increased risk of IHPS. A possible association was also found with use during late pregnancy.

EXTEND & MUSIC: Optimizing Crohn Disease Care

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As noted in recent posts (see links below), there is increased interest in showing direct mucosal healing and achieving optimal drug levels in controlling Crohn disease (CD).

  1. Clin Gastroenterol Hepatol 2014: 12: 414-422.
  2. Clin Gastroenterol Hepatol 2014: 12: 423-431.

The first study examines the rates of deep remission induced by adalimumab.  Deep remission is “defined as the absence of mucosal ulceration and CD Activity Index scores less than 150.”

Design: The data is derived from the EXTEND (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing) trial.  EXTEND was a 52-week randomized, double-blind, placebo-controlled trial of adalimumab (ADA) for adults (n=135) with moderate to severe ileocolonic CD.  All patients received open-label induction with ADA (160/80 mg at weeks 0/2), then were randomized to ongoing ADA 40 mg every other week or placebo.

Results: Rates of DR were 16% in ADA patients compared with 10% of placebo-treated patients at week 12.  By week 52, 19% of ADA patients were in DR compared with 0% of placebo-treated patients.

Key findings:

  • Analysis showed that shorter disease duration was associated with DR.  One-third of patients with CD for <2 years achieved DR.
  • Patients with DR had better outcomes than those with only mucosal healing (n=8); those with isolated clinical remission (n=19, no mucosal healing), but not DR, had similar outcomes to those with DR.  The associated editorial (pg 432) notes “symptoms will still make patients go to the emergency department, or miss work, or feel miserable, regardless of how good their mucosa looks.”
  • The authors state that during the 40 weeks after early CR, “estimated savings were $6117 for direct medical costs and $4243 for indirect costs” (total $10,360).  This monetary savings may not be offset in clinical practice by ileocolonoscopy which is not only invasive but also expensive.

Conclusion (from the authors): “Before any recommendation to adopt DR as a treatment target, establishing a clear association between achievement of DR and better long-term prognosis is necessary.”  The editorial advises against adopting DR as a treatment goal: “combining symptoms and mucosal healing into 1 end-point should be reconsidered as a measure of response to anti-inflammatory therapies.”

The second study, referenced above, examined plasma concentrations of certolizumab pegol (CZP) and endoscopic outcomes of patients with Crohn disease.

Design: The authors analyzed data (post hoc analysis) from the MUSIC (The Endoscopic MUcoSal Improvement in Patients with Active CD Treated with CZP) study. Adult patients received subcutaneous CZP (400 mg) at weeks 0, 2, and 4 followed by every 4 week treatment for 52 weeks.  Endoscopic evaluation took place at weeks 0, 10, and 54 and CZP concentrations were measured at weeks 8 and 54. At week 10, there were 45 patients analyzed and at week 54, 18 patients.

Key findings:

  • Mean CZP concentrations: 11.1 mcg/mL at week 8 (4 weeks after previous dosing) and 14.9 mcg/mL at week 54 (2 weeks after previous dosing).
  • Higher CZP concentration (by quartile values) correlated with endoscopic response (P=.0016) and remission (P=.0302) at week 10.
  • Among those with the highest CZP values, their 8-week CDEIS (CD Endoscopic Index of Severity) remission rate was 75% (12/16).  Overall, CDEIS remission was noted in 56% (25/45) at week 8.
  • At week 54, endoscopic remission correlated with plasma CZP values (P=.0206).
  • Both high CRP and high body weight inversely correlated with CZP concentrations.

Conclusion from this study: As with other anti-TNF agents, higher serum levels were associated with mucosal healing.  However, the data do not prove causality.  “It is possible that higher trough concentrations at week 8 may be a consequence of mucosal healing” rather than the reverse.

Bottomline: These two studies together show that achieving optimal long-term response correlates with therapeutic drug levels and mucosal healing.  At the same time, these studies along with many other indicate that we have along way to go in order for us to achieve these objectives consistently.

Related blog posts:

 

Camp Weekaneatit for Kids with Celiac

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From my colleague, Jeff Lewis:  “The camp is called Camp Weekaneatit, it is July 13 to July 18, overnight camp, strictly gluten-free so the kids can eat what they want without having to worry.  Its part of Camp Twin Lakes – an organization that hosts tons of medical camps.  We have kids from all over – as far away as California the last two years.  Scholarships are available.”

Anyone who tries to follow a strict gluten-free diet knows how difficult it can be to take a trip outside the home.  This camp lets kids enjoy camp without the worry about the next meal or snack.  Spread the word!

 

CampInformation 

Are you familiar with CMMR-D?

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In a recent review, CMMR-D and Lynch syndrome are reviewed (JPGN 2014; 58: 144-52). The term CMMR-D refers to constitutional mismatch repair deficiency.  This occurs when an individual inherits two MMR gene defects (rather than one gene defect in Lynch syndrome). CMMR-D can occur when a different mutation is inherited from each parent. MMR genes include MLH1, MSH2, MSH6 and PMS2.

Unlike Lynch syndrome when screening for colorectal cancer (CRC) usually starts at age 20 years or 5 years before first CRC in family, with CMMR-D screening recommendations include yearly endoscopic evaluation beginning at age 3 years or at diagnosis.  Complete management guidelines are listed in Table 4.

Digging into the COMMIT Study

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“Lies, damned lies, and statistics” –Mark Twain (who attributed this quote to Benjamin Disraeli)

Using statistics, the recent COMMIT study (Gastroenterol 2014; 146: 681-88) showed that the combination therapy of methotrexate (MTX) and infliximab (IFX) was not more effective than IFX alone. Does this result makes sense? No.

Before getting back to that question, here’s the background: this 50-week study was a randomized, double-blind, placebo-controlled trial with patients assigned to either methotrexate at dose escalated gradually to 25 mg/week (n=63) or placebo (n=62); both groups received a prednisone induction (with tapering starting at week 1) along with IFX (5 mg/kg) at weeks 1, 3, 7, 14, 22, 30, 38, and 46.  Remission was considered to be a CD Activity Index (CDAI) of <150 in individuals off prednisone.  The patients enrolled in this study were on average about 40 years of age and had similar baseline characteristics, including disease duration of more 9 years.

Amazing to me was the fact that nearly 40% of both the treatment and control group included current smokers (since smoking clearly worsens CD).

Key Results:

  • Combination therapy resulted in fewer antibodies to IFX (ATIs): 4% vs. 20% (P=.01)
  • Combination therapy resulted in higher IFX trough levels: 6.35 mcg/mL vs. 3.75 mcg/mL (P=.08); the proportion with detectable trough levels was also higher in the combination group: 52% compared with 46%.
  • Safety was similar.  “No clinically relevant hepatotoxicity was identified.” However, 14 patients did experience an increase in liver enzymes. Infusion-related reactions were infrequent: 1 in combination group, and 3 in IFX monotherapy.
  • At week 14, 76% of combination group achieved prednisone-free remission and 78% of IFX monotherapy.  At week 50, these numbers were 56% and 57% respectively.

Getting back to the question about why this does not add up as a negative study –the combination group had lower ATIs and better IFX drug levels, this usually translates into better response.  As such, the limitations of this study deserve to be scrutinized:

  • Relatively small numbers of patients
  • Objective markers like colonoscopy were not included
  • Short duration of study period.  While a 1 year study is not really all that short, some benefits of medications can take a longer time to appreciate
  • Prednisone induction may have obscured MTX benefit
  • Treatment group had long duration of disease.  Those with shorter disease duration may have a more inflammatory component to their disease and respond more favorably.

Bottomline: this study showed that the combination of MTX/IFX was not statistically-superior to IFX alone.  Given the favorable benefit on ATIs and IFX drug levels, MTX combination may still be useful, particularly in those with more recent onset of IBD.

Plus One More Reference:

Clin Gastroenterol Hepatol 2014; 12: 434-42.  This retrospective study of 425 patients (1975-2012) examined features associated with failure of medical treatment. “Patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery.  Better patient outcomes are achieved by treating CD at early inflammation stages.”

Related blog entries:

 

 

Only in Kids: Allergies Vary by Region

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From the NIH:  link to full article: http://t.co/QuVzGFPTDb

An excerpt (highlighted for emphasis):

In the largest, most comprehensive, nationwide study to  examine the prevalence of allergies from early childhood to old age, scientists  from the National Institutes of Health report that allergy prevalence is the  same across different regions of the United States, except in children 5 years  and younger.

“Before this study, if you would have asked 10 allergy  specialists if allergy prevalence varied depending on where people live, all 10 of them would have said yes, because allergen  exposures tend to be more common in certain regions of the U.S.,” said Darryl  Zeldin, M.D., scientific director of the National Institute of Environmental  Health Sciences (NIEHS), part of NIH. “This study suggests that people prone to  developing allergies are going to develop an allergy to whatever is in their  environment. It’s what people become allergic to that differs.”

The research appeared online in February in the Journal of  Allergy and Clinical Immunology, and is the result of analyses performed on  blood serum data compiled from approximately 10,000 Americans in the National  Health and Nutrition Examination Survey (NHANES) 2005-2006.

… Among children  aged 1-5, those from the southern U.S. displayed a higher prevalence of  allergies than their peers living in other U.S. regions. ..

“The higher allergy prevalence among the youngest children  in southern states seemed to be attributable to dust mites and cockroaches,”  explained Paivi Salo, Ph.D., an epidemiologist in Zeldin’s research group and  lead author on the paper. “As children get older, both indoor and outdoor  allergies become more common, and the difference in the overall prevalence of  allergies fades away.”

The NHANES 2005-2006 not only tested a greater number of  allergens across a wider age range than prior NHANES studies, but also provided  quantitative information on the extent of allergic sensitization. The survey  analyzed serum for nine different antibodies in children aged 1-5, and nineteen  different antibodies in subjects 6 years and older. Previous NHANES studies used skin prick tests to test for allergies.

The scientists determined risk factors that made a person  more likely to be allergic. The study found that in the 6 years and older  group, males, non-Hispanic blacks, and those who avoided pets had an increased  chance of having allergen-specific IgE antibodies, the common hallmark of  allergies.

Socioeconomic status (SES) did not predict allergies, but  people in higher SES groups were more commonly allergic to dogs and cats,  whereas those in lower SES groups were more commonly allergic to shrimp and  cockroaches.

Briefly Noted…Paracentesis, Hyperinsulinemic Hypoglcemia, and Hepatitis E

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Paracentesis is associated with reduced mortality in patients hospitalized with cirrhosis and ascites (Clin Gastroenterol Hepatol 2014: 496-503).  This study relied on a 2009 Nationwide Inpatient Sample database with about 8 million discharges per year.  Of the 17,771 eligible admissions, 61% underwent paracentesis, most (66%) within 1 day of admission.  “In-hospital mortality was reduced by 24% among patients who underwent paracentesis.”  The authors note that some providers may overestimate the risk of bleeding and that many have developed an increased reliance on interventional radiology. While the authors were not certain why this mortality benefit occurred, they note that patients who underwent paracentesis were probably at least as sick as those who did not.  “Patients who underwent paracentesis were actually more likely to have sepsis or acute renal failure, both markers of illness severity.”

Sirolimus helps with hyperinsulinemic hypoglycemia (NEJM 2014; 370: 1131-37).  This brief report showed that sirolimus can be an alternative to subtotal pancreatectomy.  It enabled the authors “to discontinue intravenous infusions of dextrose and glucagon in all four patients and to halt octreotide in three of four.  At 1 year of age, the four patients were continuing to receive sirolimus and were normoglycemic, without any apparent major adverse events.”  Of interest, these findings parallel the findings in adults with insulinoma who were treated with mTOR inhibitors.

Ribavirin treatment for chronic hepatitis E infection in transplant recipients (NEJM 2014; 370: 1111-20).  Retrospective uncontrolled study of 59 patients who had undergone solid-organ transplant had been treated with ribavirin at a mean dose of 600 mg for median of three months.  Median time for HEV infection prior to therapy was nine months. HEV RNA level was undetectable in 46 of 59 patients (78%) after cessation of ribavirin.

Related blog posts:

Cannabis: Feel better, Worse Crohn Disease

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To my amazement, the Georgia legislature has voted to eliminate all speed limits for those individuals with a gun permit.  After all, if you need a gun for self-defense, you might need to get somewhere quick to use it.  In addition, they have mandated that all dictionaries sold in the state to list “Obamacare” as an official synonym for the word “evil.”

The first part of this post is in jest. Today’s post is not all fiction:

While cannabis is not a frequent pediatric GI issue, it has received a lot of press of late.    A recent article has shown that cannabis is associated with worse disease prognosis in Crohn disease despite symptom relief (Inflamm Bowel Dis 2014; 20: 472-80).

Design: 313 consecutive patients (69% response of initial 461 distributed questionnaires) seen in Calgary (2008-2009) completed a structured anonymous questionnaire.  Subjects who had taken cannabis for IBD symptom relief were compared with those who had not.  Cannabis user had a mean age of 36.6 yrs compared with 40.2 yrs for nonusers.

Key findings:

  • Cannabis had been used by 17.6% of respondents to relieve IBD symptoms, mostly by inhalation (96%).  It reportedly improved abdominal pain, joint pain, and diarrhea.
  • The use of cannabis for more than 6 months at any time for IBD symptoms was a strong predictor of requiring surgery (odds ratio =5.03) after controlling for other demographic factors including tobacco smoking.

Limitations:

  1. Questionnaire honesty, though authors indicate several reasons why the number of cannabis users is likely fairly accurate.
  2. Previous surgery was higher in the cannabis users.  It is possible that patients with greater disease severity take cannabis more frequently; in this situation, cannabis would be a marker of disease severity rather than a potentially causative factor.
  3. The average patient had long-standing disease, >13 years.  Cannabis could potentially be more helpful (or less harmful) at an earlier inflammatory stage.

The study findings are in contrast to a small study previously reviewed on this blog which indicated that cannabis may improve Crohn disease: Crohn’s Research: Going to Pot | gutsandgrowth.

Take home message: For those of you planning to move to Colorado, cannabis does not cure all ills.  In this single center, tertiary care study, it was associated with a worse prognosis in adults with Crohn disease.