Joint Mobility –Not Associated with Increased Functional GI Disorders

According to a recent study (M Saps et al. JPGN 2018; 66: 387-90), joint hypermobility is not associated with an increased risk of functional gastrointestinal disorders (FGIDs).

From a school-based study of 654 children from a public school in Cali, Columbia, 148 (22.6%) were identified as having an FGID. Among this group, 136 children participated in the study along with 136 age/sex-matched healthy controls. Joint laxity was assessed to establish a Beighton score.

Key finding:

  • There was no significant difference in joint laxity between the FGID group and the control group, with OR of 1.03.

The implication of this study is that previous associations between joint hypermobility (JH) and FGIDs could be due to selection bias at tertiary care centers.  Alternatively, “it is possible that the association between FGIDs and JH exists, but it is only limited to a subset of patients that consult at specialized clinics.”

My take: This article challenges the idea that JH increases the risk of FGID.  Based on this study, if JH is a risk factor, it is hard to detect in a general population.

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Amber Cove, Dominican Republic

#NASPGHAN17 Why Rome IV Criteria are important

More information from this year’s annual NASPGHAN meeting.

This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

The following slides highlight a terrific lecture by Carlo DiLorenzo (Nationwide Children’s Hospital).  Subsequently, I’ve included slides from Miranda van Tilburg (UNC); I was unable to attend her lecture and found some of the slides via twitter.

Key points:

  • Rome IV criteria are helpful, particularly with less common presentations like rumination
  • There has been an increase in nausea.  Morning nausea can be equated as a marker of anxiety until proven otherwise.
  • There is improved wording. “After appropriate medical evaluation, the symptoms cannot be attributed to another condition” may help facilitate the diagnosis of irritable bowel syndrome, for example, in patients with IBD who are in remission.

From Miranda Tilburg:

#NASPGHAN17 Annual Meeting Notes (Part 1): Neurostimulation for RAP, PSC-IBD, Organoids

This blog entry has abbreviated/summarized these presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

William Balistreri Prize: Katja Kovaic et al. Neurostimulation for functional abdominal pain disorders in children –a randomized, double-blind, sham-controlled trial. This study enrolled 104 patients.  Lancet Gastroenterol Hepatol 2017; 2: 727-37.

Summary slide:

Fellow Research Award: Symptoms Underestimate Endoscopic Activity in PSC-IBD. Amanda Ricciuto et al. Hospital for Sick Children.

Key points:

  • In patients with IBD-PSC, clinical remission based on clinical symptoms is not reliable indicator of histologic remission.
  • Patients with PSC-IBD are more likely to have active endoscopic disease even when in “clinical remission”
  • Calprotectin levels (not PUCAIs) are helpful in confirming clinical remission.  A calprotectin <93 mcg/g was optimal level in determining clinical remission
  • Better control of disease could improve clinical outcomes (eg. colon cancer, liver progression)

Keynote Address: Organoids: Current and future promise for changing treatment of gastrointestinal and liver disorders.  James Wells Cincinnati Children’s Hospital Medical Center.

This was a terrific lecture.

  • Example of use of pluripotent stem cell usage: Diabetes. Phase 1 study has been started.
  • Organoids are in essence miniature versions of organs in a dish and with complex combination of cell types.
  • Organoids allow easier testing on these tissues for treatment and diagnosis of diseases
  • Organoids will allow for personalized testing of medications.  Some patients will respond differently.  This technology could be used to grow a specific organoid for a specific person and determine response on the organoid before giving to the patient.
  • Can engraft organoids into mice which can provide blood supply and allow larger organoids.
  • Clinical projects for organoids: Hirschsprung’s,  H pylori, Clostridium difficile, Short bowel syndrome, Fatty liver disease

Dreaded Nausea (2017)

This post provides followup to a previous post: Dreaded Nausea.

A recent study (AC Russell, AL Stone, LS Walker, Clin Gastroenterol Hepatol 2017; 15: 706-11) provides even more reasons to dread nausea.

This prospective study of 871 children with functional abdominal pain examined the comorbidity of nausea.  Followup data were collected from 392 patients at median of 8.7 years later.

Key findings:

  • At baseline, 44.8% of patients reported nausea. This group reported worse abdominal pain, somatic symptoms and depression than those without nausea.
  • At followup, “those with nausea in childhood continue to have more severe GI (P<.001) and somatic symptoms (P=.003)…as well as higher levels of anxiety (P=.02) and depression (P=.02).”  Anxiety and depression remained significant after controlling for baseline abdominal pain severity.
  • At the followup evaluation, the prevalence of any functional GI disorder (FGID) was 85 (48%) of those who had nausea at baseline compared with 77 (36%) for those without nausea at baseline.

In their discussion, the authors reiterate findings from previous work on this patient sample: “current and lifetime diagnoses of anxiety disorders are substantially higher in adolescents with a history of FAP [functional abdominal pain] compared with healthy controls (lifetime, 51% vs. 20%; current 30% vs 12%). The lifetime risk of depressive disorder is also significantly higher in those with FAP (40% vs. 16%).”  They also note some limitations in their work, including the absence of formal screening for postural orthostatic tachycardia syndrome (POTS).

My take (borrowed from authors): This study “suggests that nausea is more than just a comorbid symptom of FAP and may have a different underlying etiology” and increases likelihood of persistent symptoms as well as anxiety and depression.

Briefly noted: RJ Shulman et al. Clin Gastroenterol Hepatol 2017; 15: 712-9. This randomized, double-blind study showed that added psyllium reduced frequency (but not severity) of abdominal pain in children (n=103) with irritable bowel syndrome. Psyllium was dosed at 6 g/day for 7-11 year olds, and 12 g for 12-18 year olds. Interestingly, this study did not show that psyllium caused a difference in normal stools or other mechanistic reasons for improvement, like breath hydrogen, breath methane, intestinal permeability or microbiome composition.

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Atlanta Zoo, Bald Eagle

 

Rome IV -Pediatric Changes

What are the changes in Rome IV for children and adolescents?  JS Hyams, C DiLorenzo et al (Gastroenterol 2016; 150: 1456-68) provide a helpful review.

Key point:

The ‘dictum’ that there was “no evidence for organic disease” as an criteria for functional disorders has been dropped in favor of “after appropriate medical evaluation the symptoms cannot be attributed to another medical condition.”  This subtle change discourages excessive investigations.

The functional disorders covered in this article include

  • H1 Functional nausea and vomiting disorders: H1a -cyclic vomiting syndrome, H1b -functional nausea and vomiting (NEW), H1c -rumination syndrome, H1d -aerophagia
  • H2 Functional abdominal pain disorders: H2a -functional dyspepsia, H2b -irritable bowel syndrome, H2c -abdominal migraine, H2d -functional abdominal pain -not otherwise specified
  • H3 Functional defecation disorders: H3a -functional constipation, H3b -nonretentive fecal incontinence

Other points:

  • “There are no published data on the treatment of isolated functional nausea and isolated functional vomiting”
  • “We have eliminated the requirement of pain to fulfill the criteria for FD” [functional dyspepsia]
  • Criteria for cyclic vomiting and abdominal migraines now require only 2 episodes in a 6 month period
  • Criteria for functional constipation requires only 1 month rather than 2 months (this is true for H3b as well).  The authors endorsed the NASPGHAN expert guidelines which included “no role for routine use of an abdominal x-ray to diagnose FC.”  The guideline discourages testing for cow’s milk allergy, hypothyroidism, celiac disease and hypercalcemia in the absence of alarm symptoms.

In a separate article, MA Benninga, S Nurko et al (Gastroenterol 2016; 150: 1443-55) describe the functional disorders affecting infants and toddlers.

In my view, the article in this special edition that incorporates the most changes regards functional disorders of the biliary tree (FGBD) (PB Cotton et al Gastroenterol 2016; 150: 1420-29). This is mainly due to data showing that sphincterotomy is no better than sham treatment for patients with post-cholecystectomy pain.  “The concept of sphincter of Oddi dysfunction type III is discarded.”  In addition, for biliary pain/’gallbladder dyskinesia,’ the authors also acknowledge that the role of obtaining a gallbladder ejection fraction is “controversial.”  “Symptoms suggestive of FGBD often resolve spontaneously so that early intervention is unwarranted.”  Ultimately, the authors state that “treatment recommendations are not firmly evidence-based.”

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Owl in Our Neighborhood

Owl in Our Neighborhood

Why ImproveCareNow is Needed

A few recent articles make a strong argument for collaborative networks, like ImproveCareNow, to improve data collection to determine the most effective therapies.

  1. Kierkus J, et al. JPGN 2015; 60: 580-85.
  2. Audu GK, et al. JPGN 2015; 60: 586-91
  3. Dotson JL, et al. Inflamm Bowel Dis 2015; 21: 1109-14
  4. Saps M, et al. JPGN 2015; 60: 645-53.

A brief description of each study.

1. This study presented a multi-center randomized open-label trial of 99 pediatric patients with Crohn’s disease (CD) who were administered infliximab (IFX) along with an immunomodulator (azathioprine or methotrexate).  After a 10 week induction, 84 were randomized to either monotherapy for 54 weeks or dual therapy for 26 weeks. The authors did not find significant differences in response between the groups.  However, they reached a conclusion: “Twenty-six weeks likely represent (sic) the safe duration of combined IFX/immunomodulator therapy in our sample of pediatric patients with CD.”

2. The second study described three cases of chronic recurrent multifocal ostesomyelitis (CRMO) associated with inflammatory bowel disease.  They tried to identify all pediatric cases in UK in the last 10 years. (As an aside, I have treated one teenager with CRMO and ulcerative colitis.)

3. The third study is a retrospective single center of 30 patients with pediatric Crohn’s disease (CD) who developed intra-abdominal abscesses (IAA) over a 12-year period.  The authors note that this is “the largest single-center review of children and adolescents with CD and IAA to date.” Yet due to the small sample size, the study provides little guidance on this important medical problem; there were no predictors of successful medical or percutaneous drainage therapy.  In addition, with the increasing use of biologics, the authors note that “the issue of which patients will eventually require surgery is even less clear.” Changes in imaging (eg. MRE) and changes in medical management (eg. more enteral nutrition and less corticosteroids) are not discussed.

4. The fourth study is a comprehensive review of randomized placebo-controlled pharmacological clinical trials in children with functional abdominal pain disorders.  They found “no evidence to support the use of most commonly used drugs in children. Only 7 pharmacological RCTs on AP-FGIDs in children were found. Most studies were single center based and had a small sample size.  The methods and outcomes were heterogeneous…We found a considerable risk of bias in most studies…There is an urgent need for well-designed randomized clinical trials using age-appropriate validated outcome measures.”

Each of these studies makes a compelling argument for collaborative research networks.  The first study had a relatively small number of patients, short follow-up period, lack of blinding, and numerous methodological limitations.  How did the authors determine that 26 weeks was the time to stop dual therapy? Among adults with CD, a well-designed SONIC study (NEJM 2010; 362: 1383) showed the superiority of dual therapy during the study period.  In children, because of concerns about thiopurine safety, the best approach is still unclear. The second study identified only three patients despite examining a large population.  Similarly, the third study describes 30 patients with a common complication of CD but provides little insight.

The fourth study is a cautionary tale illustrating the lack of progress due to the absence of collaborative research.  Reports indicate a high prevalence of functional abdominal pain; one study indicated that abdominal pain affects “38% of school children weekly” (J Pediatr 2009; 154: 322-6).  In fact, studies on the high prevalence of this disorder dates back for 60 years (Apley, 1975; Apley & Hale, 1973; Apley & Naish, 1958). Despite the prevalence of this problem, the data for all of the treatments is poor.  The lack of progress in defining treatments for functional abdominal pain is multifactorial, including the following:

  • Cost: For many of the available treatments, there is not a financial incentive to conduct research.
  • Biomarker: lack of objective markers for improvement
  • Disease Stigma: many people attribute functional disorders as being due solely to psychological factors
  • Physician Champions: in pediatric gastroenterology, it took concerted physician efforts over many years to develop ImproveCareNow.  Similar physician champions would be needed to improve the outcomes for children with functional disorders

Bottomline: While ImproveCareNow has a lot of work ahead including improving data reliability and ascertaining accurate outcome measures, I think the effort is forward-thinking and will make a difference in understanding and treating children with IBD.  ImproveCareNow has more than 600 participating pediatric gastroenterologists and more than 20,000 patients. What I would like to see is a sister network to address the morbidity from functional disorders so that in 60 years (or sooner), we will be better equipped to treat children with abdominal pain that is not due to IBD.

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Fox Theater

Fox Theater

How Effective are the Treatments for Functional Abdominal Pain?

According to a recent systematic review (Korterink JJ et al. J Pediatr 2015; 166: 424-31), “there is no evidence to support routine use of any pharmacologic therapy” for pediatric functional abdominal pain (FAP).  How many pediatric gastroenterologists want to discuss this conclusion with their patients?

How did the authors reach their conclusion?

Design: The authors screened 557 articles and ultimately identified only four articles with a total of 6 studies met inclusion criteria which included the following:

  • systemic review or randomized control trial
  • children 4-18 years
  • diagnosis of FAP established with well-defined criteria
  • intervention was compared to placebo or alternative treatment

Results: All of the studies were reviewed –each received an overall quality rating by the authors as “very low.” The particular treatments included amitriptyline, peppermint oil, famotidine, miralax, tegaserod, and cyprohepatadine.  The study with the most patients had only 90 patients and the longest treatment period was 4 weeks.

In the discussion, the authors make several key points:

  • there is a lack of adequately powered, high-quality, placebo-controlled drug trials in children with FAP
  • weak evidence was found in support of peppermint oil, cyproheptadine, and laxatives at reducing pain; amitriptyline and famotidine had weak evidence supporting some improvement in global symptoms or quality of life.
  • problems with the studies: small sample sizes, poorly reported side effects, lack of follow-up, risk of bias
  • “several nonpharmacologic therapies (e.g.. hypnotherapy and cognitive behavioral therapy) have shown their efficacy in treating children with” FAP…with success rates up to 85%.  Moreover, these therapies are not hampered by severe side effects.”

Bottomline: Our office-based psychologist may be more helpful for our patients than all the medications combined.

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