Category Archives: Pediatric Gastroenterology Intestinal Disorder

High Endoscopy Complication Rate After Intestinal Transplantation

Posted on by

A recent study (J Yeh et al. JPGN 2015; 61: 636-40) indicated a high rate of endoscopy complications in pediatric patients who have undergone intestinal transplantation.

Key points:

  • Complications: In this single-center study with 1770 endoscopies (1014 sessions), the serious GI complication rate was 1.8% (32/1770).  The complications included 11 GI perforations, 13 GI bleeds, 6 GI hematomas, 1 gastric mucosa avulsion, and 1 distention from retained air. The authors’ database was not designed to capture cardiopulmonary complications.
  • In comparison, the authors note that adults without intestinal transplantation have an estimated a perforation rate of 0.09% and serious complication rates (GI and non-GI complications) of 0.15% for upper endoscopy and of 0.2% for colonoscopy. In addition, a large pediatric study of non-transplant patient endoscopies, found a perforation rate of 0.014% for EGDs and 0.028% for colonoscopies. Thus, the authors are reporting a perforation rate (11 of 1770) that is more than 20-fold higher than this pediatric study’s colonoscopy perforation rate.
  • Their techniques are well-described. For example, “for ileoscopies, 2 to 3 sites each consisting of 2 to 3 biopsies were also taken every 5 to 10 cm from the distal graft…typically surveyed up to 50 to 60 cm from the ostomy or ileocolonic anastomosis.”
  • The reasons for endoscopy were most frequently related to diarrhea/stool output in 35% and for surveillance in 32%.
  • The other interesting finding was that “of histology-proven rejections, 45% had normal-appearing endoscopies.”

The authors recommend that patients with intestinal transplantation should have endoscopy at a specialized center with teams who are intimately familiar with these children.

My take: I worry that the high complication rates reported at this center may indicate that individuals (perhaps in training) who are less familiar with the patient’s anatomy are performing many of these endoscopies.  I think individuals very familiar with the patient’s anatomy are best-suited to perform these endoscopies; this may limit some individuals at these specialized centers and may include some skilled endoscopists outside of intestinal transplant centers.

Related blog post: Something Bad is Going to Happen | gutsandgrowth

Galapagos

Galapagos

 

The Prosecution Rests…PPIs on Trial

Posted on by

For physicians who use proton pump inhibitors in a cavalier manner, a recent review (CM Stark, CM Nylund. J Pediatr 168: 16-22) provides a sobering reassessment of the potential side effects and potential complications of proton pump inhibitors (PPIs).  After finishing the article, the impression left was of a lawyer putting these medications on trial for high crimes and misdemeanors.

Here were the key points:

Infectious disease: PPI-induced hypochloridia is known to alter the gastrointestinal bacteria motif, allowing certain normally absent or depleted pathogenetic microorganisms to survive and proliferate.  This can lead to all of the following:

  • small bowel bacterial overgrowth
  • increased gastrointestinal infections (including Clostridium difficile, Salmonella, Campylobacter, and acute viral gastroenteritis)
  • pneumonia (particularly community acquired pneumonia and hospital acquired pneumonia)
  • upper respiratory infections
  • spontaneous bacterial peritonitis.

The magnitude of these associations is discussed in detail in the review.

Gastrointestinal disease: Use of PPIs has been associated with an increased incidence of the following:

  •  celiac disease which persisted after excluding prescriptions in the year preceding diagnosis (association does not prove causation)
  • benign gastric fundic polyps
  • rebound acid hypersecretion

Malabsorption: PPIs can affect absorption of multiple nutrients, though more studies are needed, particularly in the pediatric age group.

  • calcium: “there is significant evidence to suggest that PPI use can alter calcium and bone metabolism…associated with an increased risk of hip fractures in older adults….It is reasonable to hypothesize that PPI administration during adolescence and early adulthood could decrease an individual’s peak bone density.”
  • magnesium: PPI have been hypothesized to affect magnesium absorption.  “A study of 366 Canadian patients hospitalized with hypomagnesemia…found PPIs [were] associated with a 43% increased risk of hospitalization.”  More studies are needed to determine the whether this risk is truly significant.
  • iron, vitamin B12, and vitamin C absorption may be affected by PPI use.

Cardiovascular/Renal/Microbiome:

  • Cardiac: In adults, PPI use has been associated with adverse cardiac events.  The pathophysiology could have been pediatric implications.  PPIs can increase asymmetrical dimethylarginine (ADMA) which is an endogenous inhibitor of nitric oxide synthase.
  • Renal: PPIs have been associated with cases of acute interstitial nephritis
  • Microbiome: “PPIs alter the microbiome.”  Decreased diversity of the microbiome has been associated with a large number of medical conditions, including irritable bowel syndrome, inflammatory bowel disease, nonalcoholic fatty liver disease, necrotizing enterocolitis as well as many non-gastrointestinal conditions.  “The temporality of dysbiosis and subsequent disease development has  not been explored fully for most conditions.”

My take: PPIs can be life-saving and disease-altering medications.  At the same time, (per authors) “PPIs should not be prescribed without consideration for all short- and long-term side effects.”

Related blog posts:

Screen Shot 2016-01-07 at 6.33.04 PM

This Webinar Will Review Issues with Regard to Optimal PPI Usage and Includes My Esteemed Colleagues (Dr. Gold and Dr. Garza)

This NASPGHAN Webinar Will Review Issues with Regard to Optimal PPI Usage and Includes My Esteemed Partners (Dr. Gold and Dr. Garza)

“Good Job Making the Diagnosis”

Posted on by

Briefly noted: JA Leon et al. Gastroenterol 2015; 149: 1697-99.  Case report of Job syndrome (Autosomal-Dominant Hyper-IgE syndrome) mimicking Crohn’s disease in a 37 yo with perianal fistula, and weight loss. Clues to the diagnosis: “Recurrent skin abscesses and respiratory infections, eczema, marked elevation of serum IgE, eosinophilia, and mucocutaneous candidiasis are the hallmark of the infectious and immunologic features…Boils and furuncles almost always occur and characteristically lack of the usual inflammatory findings…”cold” abscesses…associated with markedly increase IgE or eosinophil levels, should always raise a suspicion for AD-HIES.”

Related blog post: Add it to the list | gutsandgrowth

Should Methotrexate Be Used For Ulcerative Colitis?

Posted on by

A recent study (F Carbonnel et al. Gastroenterol http://dx.doi.org/10.1053/j.gastro.2015.10.050, article in press; thanks to KT Park twitter feed for reference) with 111 patients provides more questions than answers.  It appears that methotrexate improved clinical remission but the overall difference is fairly small; the abstract is below.

My initial impression: Immunomodulators (including methotrexate and thiopurines) have some efficacy as monotherapy agents in patients with inflammatory bowel disease. Their role as part of combination therapy (with anti-TNF agents) has been associated with improved outcomes but how long to use combination therapy and at what dosage is still being worked out.

Here’s the abstract and a link: Methotrexate is not Superior to Placebo in Inducing Steroid-free Remission, but Induces Steroid-free Clinical Remission in a Larger Proportion of Patients with Ulcerative Colitis

Background & Aims

Parenteral methotrexate is an effective treatment for patients with Crohn’s disease but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC.

Methods

We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/week) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe, from 2007 through 2013. Patients were given prednisone (10 to 40 mg/day) when the study began, and randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary endpoint was steroid-free remission (defined as a Mayo score ≤ 2 with no item > 1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤ 2 with no item > 1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24.

Results

Steroid-free remission at week 16 was achieved by 19/60 patients given methotrexate (31.7%) and 10/51 patients given placebo (19.6%)—a difference of 12.1% (95% confidence interval [CI], –4.0% to 28.1%; P=.15). The proportions of patients in steroid-free clinical remission at week 16 were 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI, 1.1%–35.2%; P=.04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group—a difference of 9.5% (95% CI, –7.5% to 26.5%; P=.28). No differences were observed in other secondary endpoints. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P=.03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P=.006).

Conclusions

In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC.

Related blog posts:

Banning Mills

Banning Mills

Optimism for New Treatment in Inflammatory Bowel Disease: AJM300

Posted on by

Yesterday’s post on “Eternal Nutrition” had a link to podcasts on enteral nutrition as therapy for Crohn’s disease.  I listened to the podcasts and they were helpful (Enteral Therapy as Primary Therapy for Crohn’s Disease Podcast).  A few points that were made included the following:

  1. Try to have the right person teach/place the nasogastric feeding tube.  If the first experience is bad, this may make further attempts quite difficult.  At CHOP, their facility has an education center and they schedule 3-hour learning session for enteral feeds.  Teaching the teen to place the NG tube is preferred.
  2. Many pediatric gastroenterologists in U.S. are not informing their patients that enteral feedings are a treatment option.
  3. In most parts of the world, induction with enteral nutrition involves virtually 100% of diet as enteral nutrition for ~8-12 weeks.  CHOP modification involves 80-90% of calories delivered enterally, typically over an overnight drip.  If someone is not responding to enteral feeds, CHOP may increase calories delivered enterally.
  4. For maintenance with CHOP modification, gradually reduction from 7 days per week to 5 days per week is attempted.  At CHOP, they prefer hydrolysate for enteral tube feedings and think more rapid gastric emptying could be helpful.  However, the podcast state that specific formulas have not been shown to be superior in trials to date.  At CHOP, if formula is taken orally, then an intact protein formula is selected.
  5. If someone uses enteral formula for maintenance, then consideration of a gastrostomy tube (after 3 months) is reasonable.  They have not had local issues at sites due to Crohn’s disease.
  6. Resources include the Oley.org website and the Crohn’s Survival Guide.
  7. Enteral therapy seems to work in small bowel as well as colonic disease, despite early reports suggesting less efficacy with colonic disease.

———————

A recent phase II study (N Yoshimura et al. Gastroenterol 2015; 149: 1775-83) indicates that an oral antagonist of α4 integrin may be quite useful for ulcerative colitis.

This double-blind, placebo-controlled trial with 102 patients found the following:

  • A clinical response rate at 8 weeks of 62.7% in the treatment group and 25.5% for placebo)
  • Rates of remission were 23.5% in the treatment group  compared with 3.9% in the placebo group.
  • Mucosal healing were 58.8%% in the treatment group  compared with 29.4% in the placebo group.
  • No serious adverse events were noted.

In the commentary by  BG Levesque and S Ghosh (pg 1669-72), it is noted that subsequent oral integrins will be compared to vedolizumab and similar safety concerns exist; that is making sure that there are no cases of progressive multifocal leukoencephalopathy (PML) which has been associated with natalizumab therapy.  For vedolizumab, the RAMP safety monitoring program has NOT identified PML in 2884 IBD patients.

The commentary (in blue) discusses several integrins as potential therapeutic targets and outlines future therapies.

Nontargeted therapies:

  • A) Induction: corticosteroids, 5- aminosalicylates, cyclosporin, and tacrolimus
  • B) Maintenance: thiopurines, methotrexate, 5-aminosalicylates, and tacrolimus.

Targeted therapies (those in development phase in italics)

  • A) Monoclonal antibodies (induction and maintenance): tumor necrosis factor inhibitors, vedolizumab, other integrin/adhesion molecule inhibitors, interleukin-12/23 inhibitors, and interleukin-6 inhibitors.
  • B) Oral synthetic (induction and maintenance or stop and start): Jakinibs, integrin blockers, sphingosine-1-phosphate (s1P) regulators, and SMAD7 antisense oligonucleotide.

“The results of AJM300 demonstrate feasibility of such an approach, and we anticipate a proliferation of such approaches given the robust evidence supporting integrins as a target, especially if the drug can be targeted or delivered in a gut-specific manner.”

My take: There are a number of therapies being developed that are likely to transform the treatment of inflammatory bowel disease; future treatments will be more precise, more effective and have many more options.

Related blog posts:

Banning Mills

Banning Mills

 

Using Ustekinumab for Crohn’s Disease

Posted on by

From GI & Hepatology News: New targeted Crohn’s therapy performs well in phase III trial.

This study of Ustekinumab (aka Stelara) was different than previous studies (see previous gutsandgrowth blog from 2012: Ustekinumab for Crohn’s disease) in that this study targeted patients who were NOT ant-TNF failures; however, about 80% of patients had failed corticosteroids.

An excerpt:

Ustekinumab, a monoclonal antibody targeted against interleukins 12 and 23 (IL-12 and IL-23)…

 The trial, called UNITI-2, enrolled patients with moderate to severe Crohn’s disease who had failed traditional therapies but were naive to or at least had not failed a tumor necrosis factor (TNF) inhibitor…

In UNITI-2, 628 patients were randomized to placebo, 130 mg of ustekinumab in a fixed subcutaneous dose of 130 mg, or a weight-based dose of 6 mg/kg of subcutaneous ustekinumab…The primary endpoint was a CDAI reduction of at least 100 points at 6 weeks. Clinical remission at 8 weeks, defined as CDAI less than 150, was a secondary endpoint.

The primary endpoint was reached by 28.7% randomized to placebo, 51.7% of those randomized to the fixed dose of ustekinumab, and 55.5% of those randomized to weight-based dosing. The advantage for the active treatment arms was statistically significant (both P less than .001). For the secondary endpoint of clinical remission at 8 weeks, the rates were 19.6% for placebo, 30.6% (P = .009 vs. placebo) for fixed-dose ustekinumab, and 40.2% (P less than .001 vs. placebo) for the weight-based dose…

Ustekinumab was well tolerated with similar rates and types of adverse events reported in the active treatment and placebo groups.

My take: This study indicates that ustekinumab is likely to be another treatment option for patients with Crohn’s disease.

My Favorite Posts 2015

Posted on by

I want to thank all of those who have provided input to this blog this year.  Best wishes to all for a happy and healthy 2016.

Here’s my list of favorite posts in the past year:

On being a doctor:

Nutrition posts:

Gastroenterology posts:

IBD posts:

Liver posts:

Screen Shot 2015-12-09 at 8.21.20 PM

Popular Posts 2015

Posted on by

Today and tomorrow I am posting the most popular posts and my personal favorite posts from 2015.  I am labeling the most popular posts as those posts that had the highest number of visits in the past year.

Most popular posts:

Shem Creek, SC

Shem Creek, SC

‘Don’t Believe Our Study’

Posted on by

The message I inferred from a recent study (CA Siegel et al. Clin Gastroenterol Hepatol 2015; 13: 2233-40) was to disregard their results which generally showed a lack of benefit of combination therapy (aka “concomitant immunomodulator” or dual therapy) compared with anti-tumor necrosis factor (anti-TNF) monotherapy for Crohn’s disease.

Specifically, the authors state the following in their discussion:

Although our results challenge the clinical importance of combination therapy in this specific scenario, it is hard to ignore the preponderance of data to date relating to the pharmacokinetics of anti-TNF medications that support the approach of combination therapy over monotherapy.

Here’s the background for this study.  The authors performed a meta-analysis of placebo-controlled trials (n=1601 subjects) to examine the question of whether continued use of immunomodulators (IMs) would be of benefit in patients who had failed monotherapy with IMs (“IM-experienced”).  The authors note that the SONIC study showed that combination therapy (infliximab and azathioprine) was more beneficial in patients who were IM-naive than monotherapy.  This meta-analysis included data from 3 anti-TNF agents: infliximab, adalimumab, and certolizumab.

Key findings:

  • Combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio 1.02) or in maintaining a response (OR 1.53).
  • In subgroup analysis, there was a statistically-significant protective effect of baseline IM exposure versus no baseline IM exposure among those treated with infliximab.
  • Generally, combination therapy was not associated with any change in adverse reactions; however, combination therapy with infliximab had lower adverse events, which was driven by infusion reactions.

My take: This study indicates that combination therapy is likely helpful in IM-experienced patients who are starting infliximab and possibly not effective with the other anti-TNF agents.  The authors emphasize the need for well-designed, prospective, randomized, placebo-controlled trial for a definitive answer.  Until then, don’t believe their study.

Of interest: Recently I became aware of a college scholarship opportunity for young adults with IBD: Abbvie Scholarship Program.

Related blog posts:

Clever Marketing or Truth in Advertising?

Clever Marketing or Truth in Advertising?

Yosemite National Park

Yosemite National Park

Should Patients with IBS be Screened for Celiac Disease?

Posted on by

Despite widespread expert opinion that those with irritable bowel syndrome (IBS) should be screened for celiac disease, whether it is a good idea is not settled.  A recent study (RS Choung et al. Clin Gastroenterol Hepatol 2015; 13: 1937-43) showed that celiac disease has a low prevalence in US patients (mean age 61 yrs in this cohort) with IBS.

Here’s an excerpt of a summary of this report from the AGA Blog: “Should all Patients with IBS be Screened for Celiac Disease?”

Rok Seon Choung et al investigated whether subjects with positive results from serologic tests for celiac disease are frequently diagnosed with IBS or other functional gastrointestinal disorders (FGIDs).

They sent self-report bowel disease questionnaires to 7217 residents of Olmsted County, Minnesota, to collect data on symptoms compatible with functional GI disorders, including IBS, collecting data on symptoms compatible with functional GI disorders, including IBS. These symptom data were linked to surveys of undiagnosed celiac disease conducted among more than 47,000 individuals from the same region, based on results of tests for immunoglobulin A tissue transglutaminase and then endomysial antibody.

Among the 3202 subjects who completed the questionnaires and had their serum sample analyzed, 13.6% had IBS and 55.2% had some gastrointestinal symptoms.

The prevalence of celiac disease, based on serologic markers, was 1.0%. However, whereas 3% of patients with celiac disease met the criteria for IBS, 14% of patients without celiac disease met the criteria for IBS.

Abdominal pain, constipation, weight loss, and dyspepsia were the most frequent symptoms reported by subjects who tested positive for celiac disease, but none of the gastrointestinal symptoms or disorders were significantly associated with results of serologic test for celiac disease.

My take: This study along with others show that celiac disease is infrequent in patients with IBS.  Since the symptoms of celiac disease overlap with IBS, I doubt this study will dissuade practitioners from screening for celiac despite the low yield.

Also, this fall I posted several blogs on GMOs.  An interesting article (from Vox/Grist) on this subject explains how GMOs are a lot like pornography: It’s practically impossible to define “GMOs”

Leaving Work

Atlanta Sky