Category Archives: Pediatric Gastroenterology Intestinal Disorder

Is Autoimmunity Associated with Nonceliac Wheat Sensitivity?

Posted on by

According to a recent study (A Carroccio, et al. Gastroenterol 2015; 149: 596-603), patients with nonceliac wheat sensitivity (NCWS) (aka. nonceliac gluten sensitivity or wheat intolerance syndrome) are more prone to developing autoimmune disorders compared with patients with irritable bowel syndrome.

Given the difficulty identifying NCWS, the findings must be viewed cautiously; in addition, much of this study was a retrospective study.

Background: The authors identified 131 patients diagnosed with NCWS (121 female) with a mean age of 29 years.  They compared these individuals to control groups of patients with either celiac disease (CD) or irritable bowel syndrome (IBS).  In addition to the retrospective study, the authors prospectively examined 42 patients diagnosed with NCWS (2011-2014).  These diagnoses were established by double-blind placebo-controlled wheat challenge.

Key findings:

  • In the retrospective analysis, 29% of NCWS patients and 29% of CD developed autoimmune diseases (mainly Hashimoto’s thyroiditis, 29 cases) compared with a smaller proportion of subjects with IBS (4%) (P<.001).
  • In the retrospective analysis, 46% of NCWS, 24% of CD and 2% of IBS developed ANA antibodies (median titer 1:80).
  • In the prospective arm, 24% of NCWS, 20% of CD, and 2% of IBS subjects developed autoimmune disease.
  • Similarly, in the prospective arm,  28% of NCWS, 7.5% of CD and 6% of U+IBS developed ANA antibodies (median titer 1:80).
  • ANA positivity was associated with the presence of HLA DQ2/DQ8 haplotypes (P<.001).  ANA positivity, to a lesser extent, was associated with the presence of duodenal lymphocytosis (grade A histology).

The authors note that “these associations strongly suggest a celiac condition, but it must be emphasized that all the patients we included were negative for CD-specific antibodies and showed normal intestinal villi” with a gluten challenge.

Potential limitations included a selection bias of patients referred to this tertiary center.

My take: This study suggests significant overlap between CD and NCWS.  The real frequency of autoimmunity in NCWS is unclear as this study population is not likely representative of most patients who go gluten-free.

Related blog posts:

Atlanta Botanical Gardens

Atlanta Botanical Gardens

“Men Sometimes See Exactly What They Wish To See” and Gluten Sensitivity

Posted on by

For me, a recent study (AD Sabatino et al. Clin Gastroenterol Hepatol 2015; 13: 1604-12, editorial 1613-15) was particularly interesting.  While it had “positive results,” these findings were based almost entirely on the results of three patients.

In brief, this study examined 61 adults (w/o celiac disease) who believed that gluten induced intestinal and extraintestinal symptoms.  These individuals were randomized to receive either 4.375 g/day of gluten or rice starch via capsules.  This amount of gluten is equivalent to 1 sandwich or 2 slices of bread.

Findings:

  • Overall, intake of gluten significantly increased symptoms compared to placebo (P=.034), including bloating, pain, foggy mind, depression, and aphthous stomatitis.
  • Looking at a scatterplot (Figure 4), it is abundantly clear that all of these findings are driven by 3 patients.
  • “In the vast majority of patients the clinical weight of gluten-dependent symptoms was irrelevant in light of the comparable degree of symptoms experienced with placebo”
  • “Our study did not provide any progress in identifying possible biomarkers of NCGS [non-celiac gluten sensitivity]”

This type of study, with mixed conclusions, led the editorialists to quote Spock (from Star Trek):

“In critical moments, men sometimes see exactly what they wish to see.”

Then, the editorial provides a historical context of NCGS with a review of the relevant prior studies.  Other comments:

  • “These findings can be a Rorschach test of sorts, in which the viewer draws interpretations that are  based on his or her prior beliefs about NCGS.”
  • The authors note that both the gluten and the control arm likely had a significant nocebo effect (negative placebo effect),
  • “This trial, like its predecessors, seems only to contribute to the uncertainty about NCGS.”

Related blog posts:

Yellowstone Canyon

Yellowstone Canyon

 

Gastrointestinal Hemangiomas in Infancy

Posted on by

A brief study (IW Soukoulis et al. JPGN 2015; 61: 415-20) makes several useful points about gastrointestinal infantile hemangiomas. This study retrospectively analyzed 16 children (14 less than 1 yr) and described the presentation and management of gastrointestinal hemangiomas.

Key points:

  • Most were female (14/16)
  • Melana, hematochezia and anemia were typical presentations, usually within the first 4 months of life
  • 9/16 also ahd some cutaneous hemangiomas.  These lesions were located predominantly in the midgut in the distribution of the SMA. Thus, endoscopy (EGD/colonoscopy) is mainly to exclude other etiologies.
  • Imaging usually will detect these lesions (High-resolution Ultrasound, CT, or MRI)
  • 1st line treatment: Propranolol and/or corticosteroids

Related blog post:

Sandy Springs

Sandy Springs

NY Times: Cutting Sugar Improves Children’s Health in Just 10 Days

Posted on by

Perhaps this is not the best day of the year for this topic….

A recent small study of 43 children is summarized by the NY Times: Cutting Sugar Improves Children’s Health in Just 10 Days

An excerpt:

Obese children who cut back on their sugar intake see improvements in their blood pressure, cholesterol readings and other markers of health after just 10 days, a rigorous new study found.

The new research may help shed light on a question scientists have long debated: Is sugar itself harming health, or is the weight gain that comes from consuming sugary drinks and foods mainly what contributes to illness over the long term?

In the new study, which was financed by the National Institutes of Health and published Tuesday in the journal Obesity, scientists designed a clinical experiment to attempt to answer this question. They removed foods with added sugar from a group of children’s diets and replaced them with other types of carbohydrates so that the subjects’ weight and overall calorie intake remained roughly the same.

After 10 days, the children showed dramatic improvements, despite losing little or no weight. The findings add to the argument that all calories are not created equal, and they suggest that those from sugar are especially likely to contribute to Type 2 diabetes and other metabolic diseases, which are on the rise in children, said the study’s lead author, Dr. Robert Lustig, a pediatric endocrinologist at the Benioff Children’s Hospital of the University of California, San Francisco.

My take:  For a long time, I have been telling patients that if they make only one change, I would start by eliminating sugar-sweetened beverages. While this is a small study, it reinforces the view that sugar intake needs to be limited.

This post included last year’s pumpkin (Halloween 2014):  NASPGHAN Postgraduate Course 2014 -Liver Module – gutsandgrow

This year’s pumpkin:

Screen Shot 2015-10-30 at 7.22.05 PM

Why the Genetics of Inflammatory Bowel Diseases Matter Now

Posted on by

A terrific update on the genetics of inflammatory bowel diseases (DPB McGovern, S Kugathasan, JH Cho. Gastroenterol 2015; 149: 1163-76) explains why and how this information matters right now.  The article is a little difficult to read due to its review of highly technical material.

Here’s what I think were the key points:

  • Big advances in understanding the genetics started with the first genome-wide association studies (GWAS) using genome-wide single nucleotide polymorphisms (SNP) chips in 2005.  “The conceptual basis of GWAS is that most complex (ie, not single-gene Mendelian) genetic disorders are polygenic, being driven by multiple common genetic polymorphisms.”
  • “Early GWAS identified the most significant loci.”  Now, more than 200 loci associated with IBD have been identified with GWAS and Immunochip data. Table 1 lists these loci over 4 pages.  About 2/3rds of these are associated with Crohn’s disease (CD) and ulcerative colitis (UC) whereas the remaining 1/3rd are unique to either CD or UC.
  • These loci provide insight into disease mechanisms. NOD2 mutations result in “impaired activation of NF-κB” This supported “the general concept that deficiencies of innate immune cell function represent a central factor in Crohn’s disease, distinguishing it from ulcerative colitis.”
  • ATG16L1 gene mutation “establish the fact that the CD risk allele is correlated with impaired autophagy.”  This is leading directly into treatment efforts.
  • IL23R.  “The most significant association is Arg381Gln…confers a 2- to 3-fold protection against development of IBD.”  The protective effect is thought to be due to “decreased numbers of interleukin (IL)-23 dependent CD4+ Th17 and CD8+ Tc17 cells…decreasing IL-23 signaling, such as through monoclonal antibody blockade of anti-p40 or anit-p19 may be beneficial.”
  • FUT2 mutations.  These mutations affect the mucus layer in Crohn’s disease.
  • Studies in non-Caucasians highlight other susceptibility regions.
  • “Currently, sequencing of the whole exome has become not only a practical method but also a cost-effective option to identify functionally relevant variants in the protein encoding regions of the genome.”

Very Early Onset IBD:

  • Whole exome sequencing (WES) identified XIAP (X-linked inhibitor of apoptosis) in a case of boy with very early onset (VEO) IBD.  XIAP is a positive regulator of NOD2 function.  WES has also identified FOXP3, and IL10RB genes.
  • “The VEO group experiences a more severe disease course and more frequently shows a positive family history for IBD in support of higher genetic load.”  Table 2 lists ~40 genes associated with VEO.  These genes are involved in epithelial barrier function, neutropenia/defects in phagocyte function, hype-and autoinflammation, and  regulatory T cells and immune regulation.

Genetic Testing Will Impact Current Therapies and Help Explain Extraintestinal Manifestations:

  • Currently testing for TPMT variations is recommended prior to use of thiopurines due to concerns of toxicity in individuals with decreased metabolism of these medications.  However, genetic testing can identify other individuals with propensity to leukopenia (eg. NUDT15 polymorphism) and those with increase risk for pancreatitis (eg. HAL-DQA1-HLA-DRB1)
  • Primary Sclerosing Cholangitis (PSC) is associated with numerous genetic loci as well. PSC “genetically is more similar to UC than to CD.” Most other extraintestinal manifestation studies have been underpowered.
  • IBD share more genetic similarity to spondyloarthropathy (SpA) than any other immune-mediated diseases.  “The vast majority of shared susceptibility loci are concordant between IBD and SpA.”
  • With regard to psoriasis, the genetic relationship to IBD is complex.  Anti-TNF agents can cause psoriaform lesions in IBD patients.  In addition, anti-IL17a therapy, “so successful in psoriasis, appears to worsen Crohn’s disease” but not in those with a TNFSF15 variant.  Specific genotyping may help identify which patients with CD are susceptible to psoriaform lesions and those who may improve with therapy typically given for psoriasis.

My take: This article shows how understanding genetics of IBD is providing insight into pathophysiology and more personalized treatment approaches.

Briefly noted: EM Stoffel, CR Boland. Gastroenterol 2015; 149: 1191-1203. Excellent review of the genetics and genetic testing for Hereditary Colorectal Cancer.  The review includes polyposis syndromes and Lynch syndrome.

Atlanta Botanical Gardens

Atlanta Botanical Gardens

Single High-Dose Oral Vitamin D Therapy (Stoss) for Children with Inflammatory Bowel Disease

Posted on by

A retrospective study (D Shepherd et al. JPGN 2015; 61: 411-14) shows that a single high-dose oral vitamin D3 therapy can be effective for 6 months.  This study involved treatment of 76 children between 2006-2010.

Stoss vitamin D dosing used in this study:

  • < 3 yrs 200,000 IU
  • 3-12 yrs 400,000 IU
  • >12 800,000 IU

Followup levels of Vitamin D (25-OH) and calcium were checked at 1 week, 4 weeks, 3 months and 6 months..

Key finding:

  • 25-OHD >50 nmol/L (=20 ng/mL) was seen in 96.6% at 3 months and 76.4% at 6 months.  63% had a level >75 nmol/L (=30 ng/mL) at 1 month.

Bottomline: Authors noted: “Stoss therapy safely and effectively achieved and maintained a level of 25OHD > 50 nmol/L during 6 months in these children with IBD.”

Related blog posts:

Atlanta Botanical Gardens

Atlanta Botanical Gardens

What is Your Infliximab Adherence Rate?

Posted on by

I started thinking about this question after a recent study (DS Vitale, et al. JPGN 2015; 61: 408-10) examined adherence at a single pediatric center (2010-2012). Adherence indicated “those who attended >80% of scheduled infusions.” Key findings:

  • 91.4% adherence rate of patients (n=151 with >4 infusions)
  • Adherent patients (n=138) attended an average of 98% of their infusions. Nonadherent patients attended, on average, 76% of their infusions.
  • The study provided some preliminary evidence that there was greater acute care use in nonadherent patients.
  • There were no demographic features that could predict adherence pattern.

My take: One of the key advantages of infusion therapy is improved and documented adherence.  Infusions also provide opportunities to assess patient in a scheduled manner. This study shows that subsets of patients with scheduled infusions have suboptimal adherence  — another target for quality improvement!

Atlanta Botanical Gardens, Bruce Munro Exhibit

Atlanta Botanical Gardens, Bruce Munro Exhibit

 

Be Aggressive! Treating Anemia Associated with Inflammatory Bowel Disease

Posted on by

A number of recent publications have made the point that anemia is a biomarker for severe inflammatory bowel disease and undertreatment affects quality of life. Reading one of the more recent studies (IE Koutroubakis et al. Clin Gastroenterol Hepatol 2015; 13: 1760-66) brought to mind the high school football cheer: Be Aggressive!

This particular retrospective study involved 410 patients (245 with Crohn’s disease, 165 with ulcerative colitis) from 2009-2013.  This study is from the same group that published data on a somewhat smaller cohort and showed that IBD treatment alone often will not resolve anemia (Koutroubakis, IE et al. Inflamm Bowel Dis 2015; 21: 1587-93–see previous blog links).

Key findings:

  • Prevalence of anemia: 37.2% in 2009 and 33.2% in 2013
  • Anemia was associated with increased hospitalizations (P<.01), clinic visits (P<.001), telephone calls (P<.004), surgeries for IBD (P=.001), and lower quality of life scores (P<.03)

The associated editorial (pgs 1767-69) suggests that IBD-related anemia, if mild (w/in 1 g/L below normal) to treat with oral iron replacement and if moderate-to-severe, then to replace intravenously (using Ganzoni’s formula calculator). In addition, if anemia is not improving, looking for alternative explanations (e.g. vitamin B12 or folate deficiency) is recommended.

Ganzoni Equation: Total Iron Deficit = Weight {kg} x (Target Hb – Actual Hb) {g/l} x 2.4 + Iron stores {mg}.   Iron stores: { 500 if W > 35kg } & { 15 mg/kg if W < 35kg }

My take: Anemia is a biomarker for severe disease.  While treating the underlying inflammatory bowel disease, don’t forget to make sure the patient’s anemia is addressed.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Central Park

Central Park

Biosimilars -Position Statement

Posted on by

Briefly noted:

“Use of Biosimilars in Paediatric Inflammatory Bowel Disease” Position Statement. JPGN 2015; 61: 503-08.  Conclusions:

  • “IBD Porto group advocates giving high priority to performing paediatric trials with long-term followup to support” the use of biosimilars (97% agreement)
  • “Treatment of a child with sustained remission on a specific medication should not be switched to a biosimilar until clinical trials in IBD are available to support the safety and efficacy of such a change” (94% agreement)
  • “Postmarketing surveillance…in children with IBD should be a mandatory requirement.” (100% agreement)

My take: Keep this reference handy.  The lower expected costs (>30% reduction) could create pressure to change treatment before the safety/efficacy is proven.

Atlanta Botanical Gardens

Atlanta Botanical Gardens

Should All Pediatric Patients with Crohn’s Disease Continue Combination Therapy?

Posted on by

Among patients/families who are not in denial about their inflammatory bowel disease, especially Crohn’s disease, an important discussion is the use of combination therapy.  This has been discussed on this blog before (see some links below).  More data on this subject has been published and again favors the use of combination therapy (V Grossi, T Lerer, et al. Clin Gastroenterol Hepatol 2015; 13: 1748-56).

This study collected data from 2002-2014 on 502 children who participated in a prospective multicenter study. This data was derived from an observational registry rather than a randomized trial, but likely reflects real-world experience with regard to newly diagnosed patients. The authors excluded those with prior biologic therapy and prior resectional surgery.

KEY FINDINGS:

  • Children receiving combination immunomodulator (IM) treatment were more likely to have durable infliximab therapy at 1 year, 3 years, and 5 years.
  • Greater length of concomitant IMs was associated with better durability.
  • For patients who had IM > 6 months after starting infliximab (n=194), durability was 0.70 at 5 years compared with 0.55 for patients with IM <6 months (n=144), and 0.48 for those who did not receive IMs (n=135).
  • In boys, methotrexate appeared to be superior to thiopurines (P<.01): 0.98 at 5 yrs compared with 0.58.  However, there were 60 males receiving methotrexate.  In the study, only 21 females received methotrexate which limited any conclusions.

Among patients who stopped IFX, the reasons included loss of response (n=61, 43%), hypersensitivity reaction (n=41, 29%), elective (n=25, 18%), lost to f/u (n=5, 3%), and other causes (10, 7%).

The “right” dose of methotrexate as a combination agent remains unclear.  There was a wide range of dosing schedules in this study.  It is worth observing that the COMMIT study in adults found no significant difference in adults who received methotrexate in addition to infliximab compared with those receiving infliximab monotherapy.

Take-home message: In this large pediatric observational study, the use of immunomodulators increased the likely durability of infliximab.  Given prior conflicting data (particularly with regard to methotrexate), even more studies are needed to determine exactly how useful combination therapy is and when monotherapy will suffice.  From my viewpoint, I worry much more about loss of efficacy to infliximab than I worry about medication adverse effects.  As such, I will continue to inform families that combination therapy appears to improve infliximab durability.

Related blog posts:

Mount Washburn, Yellowstone

Mount Washburn, Yellowstone