Category Archives: Pediatric Gastroenterology Intestinal Disorder

Omega-3 Fatty Acids, Lipid Emulsions, and Hepatic Pathology

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Many have advocated for the use of parenteral fish oil lipids like Omegaven which are rich in omega-3 polyunsaturated fatty acids (O3FAs), though the data in support of them are limited (New lipid emulsions — lacking data to support usage …).

A recent study (J Pediatr 2014; 165: 59-64) identified seven liver-inclusive intestinal transplants who had received O3FAs.   This retrospective review study took place between 2003-2012.  These seven patients had received O3FAs for a mean of 62% of their total life span before transplant.  While these patients almost all had resolution of cholestasis (mean total bilirubin 0.7 mg/dL at time of transplant), advanced fibrosis (stage 3 or 4) was noted on explant pathology.  The histologic inflammatory scores were lower (P=.056) in comparison to O6FA group.

The authors make several important points:

  • The “results provide additional evidence that the improvement in hyperbilirubinemia following O3FA substitution therapy does not consistently produce histologic recovery of the liver.”
  • This study does not address whether comparable improvements could have been obtained from lipid restriction among the O6FA group.
  • Only 1 of 20 studies of O3FA lipid emulsion in PNALD includes hepatic histopathology as an outcome measure.

This is not the first study that indicates that liver fibrosis may persist and progress on O3FA therapy (J Pediatr 2010; 156: 327-31, J Pediatr Surg 2010; 45: 95-9, JPGN 2013; 56: 364-9).

Bottomline: Continued investigation of O3FA emulsions in PNALD is needed and assessing liver histology may be needed prior to intestinal transplantation.

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Systemic Review of Dietary Treatments for Eosinophilic Esophagitis

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A recent analysis of the literature for dietary treatment of eosinophilic esophagitis (EoE) has been published (Gastroenterology 2014; 146: 1639-48). Only 33 references out of 581 screened were included, yielding 1317 patients (1128 children and 189 adults).

Key findings:

  • Elemental diets were effective in 90.8%
  • Six-food elimination diets were effective in 72.1%
  • Allergy test-directed diets were effective in 45.5%
  • Adults responded similarly to children to dietary interventions with remission in 67.2% compared to 63.3%.

Bottomline: This study reiterates the dietary response rates from multiple previous studies. The finding that adults respond similar to children is less well-recognized, perhaps because dietary treatments are used less often in adults with EoE.

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Tofacitinib -Risks and Benefits in Rheumatoid Arthritis

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Previously Tofacitnib, an oral Janus kinase inhibitor, has shown promise as an emerging treatment for inflammatory bowel disease (Tofacitinib –a JAK Inhibitor for UC | gutsandgrowth).  So, a recent large study in tofacitinib use in rheumatoid arthritis caught my attention, specifically with regards to the potential risks of treatment (NEJM 2014; 370: 2377-86).

This double-blind study randomly assigned 958 patients (mean age ~49 years) to receive 5 mg or 10 mg of tofacitinib twice daily or weekly methotrexate.  This study, called ORAL Start, examined the effectiveness of these drugs over a 24 month period in patients with active moderate-to-severe rheumatoid arthritis naive to therapeutic doses of methotrexate.

Key findings:

  • Among tofacitinib patients, 25.5% (5 mg group) and 37.7% (10 mg group) had an ACR 70 response at 6 months compared with 12.0% of methotrexate patients.  Results at 12 and 24 months were similar (Figure 1)
  • Adverse effects:
  1. 4% of tofacitinib patients developed herpes zoster compared with 1.1% of methotrexate patients
  2. 5 tofacitinib patients developed cases of cancer (three cases of lymphoma) compared with 1 case among patients receiving methotrexate
  3. Tofacitinib was associated with decreases in neutrophil/lymphoctye counts, increases in creatinine levels, increases in aminotransferases, and increases (16-22%) in LDL/HDL cholesterol levels
  4. Four deaths were noted among patients treated with tofacitinib compared with none in the methotrexate patients.

Related blog post: Source Article: Methotrexate Safety | gutsandgrowth

Anti-TNF Agents in Pediatrics Have NOT Been Shown to Cause Lymphoma

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This blog title is supported by a recent publication (Clinical Gastroenterology and Hepatology: http://dx.doi.org/10.1016/j.cgh.2014.01.021)

Here’s the abstract -(I emphasize a key point with bold) or check out the link above:

Background & Aims

Many physicians hesitate to recommend anti–tumor necrosis factor (TNF) therapy for pediatric patients with inflammatory bowel disease (IBD) because of concerns about risk of infection and cancer. We performed a systematic review to quantify the incidence of serious infection, lymphoma, and death among pediatric patients with IBD who received anti-TNF therapy. These values were compared with those expected from other treatments, from adults with IBD, and from the general pediatric population.

Methods

We searched MEDLINE, EMBASE, the Cochrane Collaboration, and Web of Knowledge for studies of infliximab therapy for children with ulcerative colitis or Crohn’s disease, or adalimumab therapy for children with Crohn’s disease. Standardized incidence ratios (SIRs) were calculated, comparing rates of infection and cancer among pediatric patients exposed to anti-TNF agents vs expected rates from pediatric patients not exposed to anti-TNF therapies or adult patients exposed to anti-TNF agents. Our analysis included 5528 patients with 9516 patient-years of follow-up evaluation (PYF).

Results

The rate of serious infections among pediatric patients treated with anti-TNF agents (352/10,000 PYF) was similar to that of pediatric patients who received immunomodulator monotherapy (333/10,000 PYF; SIR, 1.06; 95% confidence interval [CI], 0.83–1.36), but significantly lower than the expected rate for pediatric patients treated with steroids (730/10,000 PYF; SIR, 0.48; 95% CI, 0.40–0.58) or adults treated with anti-TNF agents (654/10,000 PYF; SIR, 0.54; 95% CI, 0.43–0.67). Five treatment-related deaths occurred (4 from sepsis and 1 from arrhythmia). Two patients developed lymphoma (2.1/10,000 PYF). This value was similar to the expected rate of lymphoid neoplasia in the entire pediatric population (5.8/100,000 PYF; SIR, 3.5; 95% CI, 0.35–19.6), and lower than the population of pediatric patients receiving thiopurine monotherapy (4.5/10,000 PYF; SIR, 0.47; 95% CI, 0.03–6.44), and among adults treated with anti-TNF agents (6.1/10,000 PYF; SIR, 0.34; 95% CI, 0.04–1.51).

Conclusions

Based on a systematic review, the risk of lymphoma was no greater among children with IBD who received anti-TNF therapy than those treated with other IBD therapies or adults treated with anti-TNF agents. The rate of serious infection was significantly lower among pediatric patients with IBD treated with anti-TNF agents than those treated with steroids, or adults with IBD who received anti-TNF therapy.

My take: This study shows that the concern for malignancy with anti-TNF agents (monotherapy) is often disproportionate to the true risk.  At the same time, much longer followup will be needed to assess the benefit and harm of these agents over decades.

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Celiac Disease Risk -TEDDY Study

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“The Environmental Determinants of Diabetes in the Young (TEDDY) is a multinational study that follows children at high genetic risk for type 1 diabetes, with the development of celiac disease as a secondary outcome.”  A recent publication provides excellent data with regard to the longitudinal risk of developing celiac disease (CD) (NEJM 2014; 371: 42-9).

Methods: 424,788 newborns were screened for at-risk HLA genotypes (from 2004 to 2010) in four countries (U.S, Finland, Germany, and Sweden).  21,589 had one of nine HLA genotypes of interest to the investigators –>8677 infants were enrolled in the study; 6403 of this group had one of the four HLA genotypes reported in this study:

  1. DR3-DQ2 homozygotes
  2. DR3-DQ2/DR4-DQ8
  3. DR4-DQ8 homozygotes
  4. DR4-DQ8/DR8-DQ4

Median follow-up: 60 months

Definitions for study:

  • Celiac autoimmunity: presence of tTG antibodies on two consecutive tests at least 3 months apart
  • Celiac disease: CD diagnosis based on biopsy (Marsh 2 or higher) or persistently high tTG (≥100 units) on at least two tests at least 3 months apart

Key findings:

  • Overall 786 children developed celiac autoimmunity (12%) and 291 had confirmed CD.
  • Children with DR3-DQ2 homozygosity had more than 5 times the risk of CD than the lowest-risk groups; in addition, the risk was 2.5 times more than the risk for a heterozygote (single DR3-DQ2) haplotype.
  • By 5 years of age, celiac autoimmunity developed in 26% and 12% respectively among children with DR3-DQ2 homozygosity  and in 11% and 3% of those children with DR3-DQ2 heterozygosity.
  • Residence in Sweden increased risk for CD with hazard ratio of 1.9.  The fact that residents with same genetic haplotypes had increased risk suggests that an environmental factor is playing a role.  It was noted that these children were given gluten-containing cereals at the earliest age.
  • CD was more common in females with HR of 2.16 (P<0.001) and in those with family history of CD HR 2.95 (P<0.001)

Take-home message: This prospective TEDDY study is providing useful information about how likely an individual with a genetic predisposition will develop CD and how quickly this develops.

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More Data on Early-Onset Pediatric Inflammatory Bowel Disease

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In 2009, a large prospective database involving Italian Pediatric Gastroenterologists was established.  A recent study describes the classification (Paris) and phenotype of early-onset pediatric inflammatory bowel disease (EO-IBD) (Inflamm Bowel Dis 2014; 20: 597-605).

In 506 consecutive patients, 224 had Crohn’s disease (CD), 245 ulcerative colitis (UC) and 37 IBD-unclassified.

Key findings:

  • 11% were aged 0-5 years, 39% 6-11 years, 50% were 12-18 years.
  • UC was more frequently diagnosed in 0-11 years of age whereas as CD was more common in 12-18 years.
  • EO-Crohn’s showed more frequent isolated colonic disease
  • EO-UC noted 62% with pancolitis compared with 38% in 6-11 years and 31% in 12-18 year group

Take-home message: The authors conclude that “EO-IBD exhibits an extensive phenotype and benefit from aggressive treatment strategies, although surgical risk is similar to later-onset disease. A family history for IBD is not common in EO disease.”

No Habla Appendicitis

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Before today’s blog, I wanted to state that our physicians now can treat Clostridium difficile with fecal microbiota transplant (would have been more relevant to yesterday’s blog: “Gut Microbiome”) :

GI Care for Kids is one of the few places in the region to offer this capability for children (thanks to Jeff Lewis for working to navigate the logistics/regulatory burdens).

Today’s blog: Though physicians make efforts to combat language barriers with translators, the personal connection between physicians and patients is undoubtedly weakened in those with limited English proficiency LEP).  Recently, one of my emergency room colleagues explained that he had ordered a CT scan on a young man in part due to his hispanic ethnicity and concern that this would lead him to overlook a diagnosis of appendicitis.  According to a recent study, my emergency room colleague was right –hispanic ethnicity and language barriers increased the risk for appendiceal perforation (J Pediatr 2014; 164: 1286-91).

The researchers performed a secondary analysis of a prospective, cross-sectional, multi center study of children aged 3-18 years who presented with abdominal pain/possible appendicitis (2009-2010) at 10 tertiary care pediatric emergency departments in the U.S.

Results:

  • Of the 2590 patients enrolled, 1001 (38%) had appendicitis.
  • Hispanics with LEP had an odds ratio of 1.44 of having appendiceal perforation.  In addition, these patients were less likely to undergo advanced imaging (OR 0.64)

Bottomline: Patients/families who speak English are more likely to communicate the severity of their medical problem.  Those with limited English proficiency are at increased risk for complications and this extends beyond perforation with appendicitis.

Related blog post: How much radiation from your CT scanner? | gutsandgrowth

New Biomarker for Crohn’s Disease (Plus Two)

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A recent study identifies a new biomarker for Crohn’s disease (CD) (Inflamm Bowel Dis 2014; 20: 1037-48).

The authors examined a cohort of 208 newly diagnosed pediatric CD and 43 non-IBD controls for ileal/rectal expression of FcγRIA mRNA.  In addition, in a smaller cohort of 26 newly diagnosed CD patients, 83 established CD patients and 30 non-IBD controls the authors measured peripheral blood polymorphonuclear neutrophil (PMN) CD64 index.

Key findings:

  • Ileal FcγRIA mRNA expression was significantly elevated in CD compared with non-IBD controls
  • PMN CD64 was significantly elevated in CD compared with non-IBD controls and correlated with mucosal injury as measured by the simple endoscopic score for CD.
  • Patients in clinical remission with a PMN CD64 <1 had a high rate of sustained remission (95%) whereas only 56% had sustained remission if PMN CD64 was >1.

Take-home point: This study shows in pediatrics, as in adults IBD patients, that PMN CD64 index is associated with mucosal inflammation; high levels are associated with clinical relapse.  Serum biomarkers are likely to complement stool biomarkers like fecal calprotectin.

One other point the authors make: “studies have found that 57% to 59% of CD have concurrent IBS.”  Thus, there is a need for biomarkers to distinguish whether patients with clinical symptoms are experiencing an inflammatory relapse.

Related blog post: Calprotectin: Part of diagnostic algorithm for IBD …

Two other studies in same issue:

“Alterations in the Intestinal Microbiome (Dysbiosis) as a Predictor of Relapse After Infliximab Withdrawal in Crohn’s disease” pages 978-86.  N=33 CD patients. Key finding: “CD-associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal.”

“Tissue Studies in Screened First-degree Relatives Reveal a Distinct Crohn’s Disease Phenotype” pages 1049-56. N=38 asymptomatic relatives. Key finding: based on histologic scoring 61% were normal, 26% had minor lesions, and 13% had evidence of active disease. This study indicates that screening relatives may identify a subset with early biologic disease.

What I Didn’t Know About Vitamin B12 and Crohn’s Disease

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This month I learned from a recent publication (Inflamm Bowel Dis 2014; 20: 1120-23) that Crohn’s disease without ileal resection does not seem to increase the risk of Vitamin B12 (cobalamin) deficiency.  To reach this conclusion, the authors did an extensive literature search and identified 42 relevant articles with 3732 IBD patients.

Key findings:

  • Ileal resections >30 cm were associated with B12 deficiency.
  • Resections <20 cm were not associated with B12 deficiency; whereas the findings were inconsistent when resections were 20-30 cm.

Take home message:  Crohn’s disease, regardless of disease location, did not increase the risk of B12 deficiency in the absence of ileal resections >20 cm.

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