Category Archives: Pediatric Gastroenterology Intestinal Disorder

Efficacy and Safety of Odevixibat with Alagille Syndrome (ASSERT Trial)

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N Ovchinsky et al. The Lancet Gastroenterology & Hepatology, Volume 9, Issue 7, 632 – 645. Open Access! Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

Methods: “The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries” with 52 patients (enrolled 2021-2022). “The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0–4) from baseline to weeks 21–24.” The treatment group received odevixibat 120 µg/kg per day.

Key findings:

  • There were improvements in both scratch scores and bile acid concentrations
  • There were improvements in sleep parameters including falling asleep and ability to sleep without a caregiver
  • Adverse events: diarrhea was reported in ten (29%) of 35 patients who received odevixibat and in one (6%) of 17 patients who received placebo; all cases were mild in severity and no cases of diarrhea led to treatment interruption or discontinuation

Scratch Scores:

Bile Acid Levels

Other points:

  • Overall, 50 (96%) of the 52 patients chose to enter the open-label extension study
  • The authors note that this is the first randomized placebo-controlled trial for Alagille syndrome
  • A direct comparison of odevixibat and maralixibat in patients with Alagille syndrome is complicated by differences in study design and endpoints across the their studies

My take (borrowed in part from authors): “As pruritus is a major driver of liver
transplantation in patients with Alagille syndrome, these results suggest that odevixibat could have the potential to delay or prevent liver transplantation”

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Hollywood Beach, FL

Safety of JAK Inhibitors Compared to Anti-TNF Agents

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C Crist. GI & Hepatology News; 11/20/24: In IBD Patients, No Increased Risk for MACE Seen for JAK Inhibitors vs Anti-TNF

Background: There have been concerns that JAK inhibitors (JAKi), like tofacitinib (Xeljanz) and upadacitinib (Rinvoq) could increase the risk of major adverse cardiovascular events (MACE); as such, the FDA has placed warnings on these medications (see blog post: FDA Slaps Restrictions on JAK Inhibitors Over Serious Safety Risks).

An excerpt:

According to a study presented at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting, .

Alsakarneh and colleagues conducted a retrospective cohort study using the TriNetX database to identify adult patients with IBD who were treated with JAKi or anti-TNF therapy after diagnosis. After matching patients in the JAKi cohort [n=3740] with patients in the anti-TNF cohort [n=3740], the research team looked for MACE and VTE within a year of medication initiation…

After excluding those with a history of a prior cardiovascular event, 57 patients (1.76%) in the JAKi cohort developed MACE, compared with 63 patients (1.94%) in the anti-TNF cohort. There weren’t significant differences between the groups in MACE (adjusted hazard ratio [aHR], 0.99) or VTE (aHR, 0.9).

Among patients aged ≥ 65, 25 patients (5.3%) in the JAKi cohort developed MACE, as compared with 30 patients (6.4%) in the anti-TNF cohort.

My take: Several studies now have not identified an increased risk of JAKi compared to other therapies for IBD. Perhaps, this will lead to a change in labeling by the FDA which has stated that JAKi should be used only in those with prior anti-TNF failure.

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This “bulging squares” illusion has straight lines across and vertically when you are right in front of it.

Efficacy of Mirikizumab in Moderate-to-Severe Crohn’s Disease (VIVID-1 Study)

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M Ferrante et al. The Lancet 2024; https://doi.org/10.1016/S0140-6736(24)01762-8. Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn’s disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study

Methods: VIVID-1 was a global phase 3, randomized, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study which enrolled 1150 patients with moderate-to-severe Crohn’s disease. There were three treatment groups: mirikizumab group, ustekinumab group, and placebo group. In each group, 48-49%were considered “biologic-failures” including 45-46% who were anti-TNF failures.

Key findings:

Discussion points:

Early treatment effect: “Symptomatic improvement was evident as early as week 4 accompanied by a statistically significant reduction in high-sensitivity CRP and faecal calprotectin, and endoscopic response was seen at week 12.”

Compared to ustekinumab: “Mirikizumab reached non-inferiority versus ustekinumab for clinical remission by CDAI at week 52…mirikizumab showed statistically significantly greater improvements from baseline in fecal calprotectin and CRP compared to ustekinumab.
In addition, a greater percentage of patients reached the combination endpoint of endoscopic response and clinical remission by CDAI at week 52.”

Comparison across treatment trials: “. At week 52, 45∙4% of patients treated with mirikizumab met the endpoint of clinical remission by CDAI in the treat-through analysis with composite endpoint, 54∙1% met the endpoint in the treat-through analysis, and 64∙3% met the endpoint in the responder analysis. This example, with a range of nearly 20% percentage points depending on analysis type, shows the profound limitations in comparing
unadjusted outcomes across phase 3 trials.” The authors note other differences in trial design between VIVID-1 and SEQUENCE (risankizimab) and state “no conclusions on
relative efficacy can be drawn.”

My take: This study shows that mirikizumab is effective in adults with moderate-to-severe Crohn’s disease with and without prior biologic treatments. Pediatric studies are underway.

Case Study: Pediatric Emergency from Magnet Ingestion

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G Prasad, V Jain. N Engl J Med 2024;391: e48. Small-Bowel Obstruction and Intestinal Fistula from Accidental Ingestion of Magnets

Case presentation excerpt:

A previously healthy 18-month-old girl was brought to the emergency department with sudden-onset abdominal distention that had been preceded by 3 days of diarrhea and 1 day of vomiting…an emergency exploratory laparotomy was performed. An ileocecal fistula (Panel B, circle) created by the union of three magnetic beads was identified (arrow, cecum; asterisk, ileum), and dilated loops of bowel were noted. The bowel was repaired. The patient was discharged after five days.

My take: There are a lot kids admitted for multiple magnet ingestion. Even in well-appearing children, due to concerns for complications, they are often observed until progression of the magnets. However, it does seem that many do not advance well after working their way to the cecum.

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Understanding Trichuriasis (Whipworm) in Young Children: A Case Study

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G Ding et al. N Engl J Med 2024;391: e34. DOI: 10.1056/NEJMicm2406623. Trichuriasis

Case report: A 2-year-old boy from a rural village in China was brought to the pediatric clinic with a 6-month history of diarrhea and poor weight gain. Laboratory studies showed iron-deficiency anemia, eosinophilia, and occult blood in the stool.

The worms, which were 3 to 4 cm in length, were identified as Trichuris trichiura — also known as human whipworm infection…Trichuriasis results from the ingestion of soil contaminated by whipworm eggs. Adult worms mature in the large intestine and affix themselves there by threading into the mucosa. Trichuriasis is usually asymptomatic but may result in diarrhea and growth retardation in cases of heavy infection, especially in young children. The child’s diarrhea resolved after treatment with albendazole.

CDC Link: Trichuriasis “The adult worms (approximately 4 cm in length) live in the cecum and ascending colon… The females begin to oviposit 60 to 70 days after infection. Female worms in the cecum shed between 3,000 and 20,000 eggs per day. The life span of the adults is about 1 year.”

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Dr. Neha Santucci: Management of DGBIs in the Post-Pandemic Era (Part 2)

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Recently, Dr. Neha Santucci gave our group an excellent update on disorders of gut-brain interaction.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of her slides.

Key points:

  • Atlantis study showed that amitriptyline reduces IBS pain (Related blog post: Atlantis Study: Possibly Best Evidence That Tricyclics May Help Irritable Bowel)
  • Dr. Santucci reviewed the evidence for linaclotide, cyproheptadine, mirtazapine, prucalopride, and aprepitant. The latter was effective for CVS but not functional nausea.
  • Placebo has been shown to have some beneficial effects in DGBIs; this affects the results of clinical trials
  • Ginger may be beneficial for nausea
  • Intrapyloric botox has been associated with improvement in functional dyspepsia. Improvement did not correlated with gastric emptying
  • Percutaneous electrical nerve field stimulation (PENFS) is associated with improvement in multiple aspects of functional disorders including pain, nausea, somatization, sleep and anxiety.
  • The improvements in abdominal pain and functional disability with PENFS are still present at least 6-12 months afterwards
  • PENFS can be repeated and has similar effectiveness
  • PENFS can be used in children >8 yrs, can be used with other treatments (pharmacologic, psychologic, or dietary).
  • PENFS can be used as prophylaxis of CVS
Non-pharmacologic Treatments
Lancet Gastroenterol Hepatol 2017; 2: 727-737.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Dr. Neha Santucci: Management of DGBIs in the Post-Pandemic Era (Part 1)

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Recently, Dr. Neha Santucci gave our group an excellent update on disorders of gut-brain interaction.  My notes below may contain errors in transcription and in omission. Along with my notes, I have included many of her slides.

John Apley’s monograph The Child with Abdominal Pains provided an early understanding of the prevalence of DGBIs.
An increase in DGBIs occurred with COVID.
This study in adults showed a greater increase in functional dyspepsia compared to IBS.

DGBIs occur in Children with Down syndrome. This cohort showed high rates of functional constipation (36%), irritable bowel syndrome (14.9%), functional dyspepsia (12.3%) and aerophagia (5.3%).
DGBIs were common after surgery for malrotation
  • Development of DGBIs is influenced by psychological factors, early life events, chronic stress, gut motility, inflammation, mucosal immune activation and altered gut microbiota
  • DGBIs are associated with altered brain networks
  • DGBIs are associated with a number of comorbidities including mental health disorders, joint hypermobility, headaches, POTS, musculoskeletal pain, disordered eating, and poor sleep
  • Individuals with DGBIs are at increased risk of eating disorders including ARFID. Presence of ARFID with DGBIs has been associated with more anxiety, depression, ADHD and sleep disturbance
  • Poor sleep in previous night is associated with increased pain the next day in individuals with DGBIs
  • DGBIs are common in children with organic diseases, including IBD, EoE, Celiac disease, Recurrent Pancreatitis, Malrotation and Anorectal disorders
  • Up to 50% of pediatric GI visits are for functional disorders and ~25% of all children have DGBIs
  • Strive to make a positive diagnosis (rather than simply a diagnosis of exclusion)
  • Avoid excessive testing
  • Dyspepsia and gastroparesis are not distinct disorders and likely exist on a spectrum (some of the same treatments for both)
  • First treatment goals: develop a good rapport with family and focus on improved functioning
Children with DGBIs had more problems with coping skills.
Individuals with DGBIs are at increased risk of eating disorders including ARFID. Presence of ARFID with DGBIs has been associated with more anxiety, depression, ADHD and sleep disturbance.
Initial treatment needs to address these questions

Related blog posts:

-“The more time the doctor spends on the history, the less time he is likely to spend on treatment.”

-“Doctors who treat the symptoms tend to file a prescription. Doctors who treat the patient are more likely to offer guidance.”

-“It is a fallacy that a physical symptoms always has a physical cause and needs a physical treatment.”

-“Anxiety like courage is contagious.”

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Case Report: Cat Scratch Colon in a Young Patient

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A Watson et al. JPGN 2024;79:1081–1083. Cat scratch colon in a patient with very early-onset Crohn’s disease with diverting ileostomy

Case report: This image is from the ascending colon of a 12 yo with Crohn’s disease sp diverting ileostomy.

“Cat scratch colon refers to the rare endoscopic finding of erythematous linear breaks that arise spontaneously, typically in the ascending colon and/or cecum, resembling scratches made by a cat, on otherwise unremarkable mucosa…It is presumed to be a benign condition likely caused by barotrauma from air insufflation during colonoscopy in a colon with altered elasticity or when the rate of insufflation exceeds the rate of air passage, such as in a diverted colon.2, 3“

My take: Surprisingly, the cat scratch colon finding is not consequential.

One Family’s Tragic Loss Prompted Widespread Interest in Organ Donation

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Los Angeles Times, Corinne Purtill, September 24, 2024: 30 years later, a family’s loss gives life to others

An excerpt:

For the Green family, the memory of Oct. 1, 1994 is many things at once: the date of their greatest pain and their finest hour; a day of unspeakable loss and life-giving gifts.

It is the date their 7-year-old son, Nicholas, died in an Italian hospital, two days after being shot during an attempted robbery on a family vacation from California…

Seven people, five of them teenagers, received Nicholas’ corneas, kidneys, liver, heart and pancreas. The family’s story prompted a surge in interest that continues to drive new donor registrations in Italy…

At the time, Italy had one of the lowest organ donation rates in Western Europe. The Greens’ decision, along with the awful circumstances of the boy’s death, led to a swell of media attention across Italy…The year before Nicholas’ death, 6.2 people per million in Italy donated their organs. Ten years later, as the story circulated and the numbers of parks, playgrounds and streets in Italy named after Nicholas grew, the number had tripled to nearly 20 people per million…

Over the years, members of the family have made dozens of trips to Italy to speak on behalf of organ donation and to check in on the people whose lives were saved by their loss…five are still living. His liver recipient, who was 19 at the time of the transplant, went on to marry and have children. The Greens have met her eldest son. His name is Nicholas.

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Risk of Eating Disorders with Dietary Therapy of Functional Abdominal Pain

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L Sims et al. JPGN 2024;79:1040–1046 Open Access! Eating concerns in youth with functional abdominal pain disorders

This retrospective cohort included 270 adolescents/young adults who attended an intensive, interdisciplinary pain treatment program, including 135 youth with functional abdominal pain (FAP) and an age- and gender-matched control group with a primary pain diagnosis of chronic headache.

Key findings:

  • Limitation of this study: The population attending this intensive pain program is NOT representative of typical outpatient setting
  • A history of an eating disorder was more common with FAP than in those with chronic headache (15.4% vs. 5.9%)
  • In this cohort, patients with FAP compared to patients with chronic headache had higher rates of prior exclusion diets to manage their symptoms (46% vs. 22%, p = 0.007), and prior requirement enteral or parenteral feeds (18% vs. 1.5%, p = 0.001)
  • The study found a significant association between a history of exclusion diets and meeting criteria for ARFID. “With regard to ARFID, the prevalence of patients in both groups who met diagnostic criteria (FAP: 50%; chronic headache: 36%) was also significantly higher than estimates from the general school-aged population (3%)”
  • Patients with FAP were also more likely than patients with chronic headache to be diagnosed with postural orthostatic tachycardia syndrome ([POTS]; 46% vs. 30%) and have a history of food allergies or intolerances (43% vs. 25%)
  • Significantly more adolescents with FAP (n = 68) than chronic headache (n = 45) had lost 4.5 kg or more, p = 0.004

My take: Most treatments for FAP, including dietary treatment, have some inherent risks. In patients placed on dietary therapies, screening and/or discussing the risk of dietary restriction need to be considered.

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