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“A Good Doctor Knows When to Bend The Rules”

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Yesterday’s post, Cholangiocarcinoma Risk in Pediatric PSC-IBD Plus one, was updated with the following caveats:

At the same time, the authors acknowledge limitations including a highly-selected patient population (selection bias) and relatively small number of patients. The absolute increase in risk for cholangiocarcinoma is not known. This study did not provide an estimate of the number of patients with IBD-PSC who develop cholangiocarcinoma; it only provides data on those with cholangiocarcinoma (thus no denominator to establish risk).

Daniela Lamas, NY Times 4/20/25 (likely has a paywall): A Good Doctor Knows When to Bend The Rules

An excerpt:

“My patient had been intubated with Covid-19 for weeks, her lungs growing stiffer each day. Her sons held vigil at the bedside, pausing only to critique the nurses and health care team. They didn’t like the way the nurse turned their mother. They demanded yet another course of antiviral treatment for Covid-19…The son pulled a pill bottle from his backpack. It was a mixture of herbs that he had ordered off the internet. He wanted me give the supplement to his mother through her feeding tube, along with her other medications…

Doctors may agree to give their patients probiotics because they are harmless, even though the evidence for their effectiveness is weak in most cases. They might prescribe an unnecessary antibiotic. They might even agree to spread out the timing of pediatric vaccinations at a family’s insistence...

For Dr. Brown…he could justify prescribing the drug to build rapport…Dr. Van Scoy sees acceding to requests for unproven medicines as a “slippery slope.” When doctors prescribe medications that they don’t believe in, even ones that pose little risk to the patient, it can cost them the trust of their colleagues…

But when distrust is so entrenched, as is the case in the United States now, that ideal might not be achievable — especially in our conventional clinical practices where doctors have some 15 minutes with each patient…

We ask our patients to trust us implicitly, to believe our diagnoses and to undergo courses of treatment they might not understand. This doesn’t mean that we need to give patients whatever they want just to level the playing field. But we can take their requests seriously, even if we wouldn’t have considered them otherwise.”

My take: In the pediatric GI realm, I am often asked to do low yield procedures (eg. esophagogastroduodneoscopy, colonoscopy), low yield imaging (eg. MRI, CT scans), allergy testing as well as numerous dubious treatments.

One measure of how likely physicians in our group are at ‘bending’ to patient wishes is evident in study that we did looking at the yield from colonoscopy. Among 16 physicians, the diagnostic yield ranged as low as 22% to as high as 86% with an overall diagnostic yield of 48% for colonoscopy. Thus, it is clear that physicians have widely different approaches in accommodating family pressures.

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Phuket, Thailand
Floating flowers in large vase

Cholangiocarcinoma Risk in Pediatric PSC-IBD Plus one

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B Kaj‐Carbaidwala et al. J Pediatr Gastroenterol Nutr. 2025; 80:450–454. Determining the time to cholangiocarcinoma in pediatric‐onset PSC‐IBD

Background: “Cholangiocarcinoma is a devastating disease, with up to 80% mortality and limited treatment options…A large retrospective cohort study reported that cholangiocarcinoma occurred in 1000 per 100,000 (1%) of children with PSC, with all occurring in children over 15 years of age and at a median of 6 years after the PSC diagnosis…Primary sclerosing cholangitis (PSC) is associated with a 400× increased risk of cholangiocarcinoma.”

Methods: Review of n = 175 studies resulted in a cohort of n = 21 patients with pediatric‐onset PSC‐IBD‐cholangiocarcinoma

Key findings:

  • The earliest diagnosis of cholangiocarcinoma was made at 14 years of age.
  • 14% of of patients with pediatric‐onset PSC/IBD developed cholangiocarcinoma within the first 6 months of the second diagnosis
  • 23% of patients with pediatric‐onset PSC/IBD developed cholangiocarcinoma within the first year of the second diagnosis
  • 38% of patients with pediatric‐onset PSC/IBD developed cholangiocarcinoma within the first 2 years.
  • 50% of patients with pediatric‐onset PSC/IBD developed cholangiocarcinoma within the first 7 years
  • 50% of patients were between 14 and 25 years old when diagnosed with cholangiocarcinoma

Based on these data, the authors recommend screening for cholangiocarcinoma in this population of pediatric patients with IBD-PSC. Screening would include ultrasound or magnetic resonance cholangiopancreatography along with serum cancer antigen 19‐9 screening every 6–12 months. At the same time, the authors acknowledge limitations including a highly-selected patient population (selection bias) and relatively small number of patients. The absolute increase in risk for cholangiocarcinoma is not known. This study did not provide an estimate of the number of patients with IBD-PSC who develop cholangiocarcinoma; it only provides data on those with cholangiocarcinoma (thus no denominator to establish risk).

My take: Children, particularly adolescents, with IBD-PSC are at increased risk for both cholangiocarcinoma and colorectal cancer. The optimal surveillance strategy is still unclear. However, particularly in adolescents, I would favor yearly ultrasound and CA 19-9 for cholangiocarcinoma along with a low threshold for frequent colonoscopy (see ESPGHAN guidelines below).

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In the news: AP 5/4/25: Cuts have eliminated more than a dozen US government health-tracking programs “U.S. Health Secretary Robert F. Kennedy Jr.’s motto is “ Make America Healthy Again,” but government cuts could make it harder to know if that’s happening…..Among those terminated at the Centers for Disease Control and Prevention were experts tracking abortions, pregnancies, job-related injuries, lead poisonings, sexual violence and youth smoking, the AP found.”

Anantara Resort, Mai Khao Phuket

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Menetrier’s Disease in a Pediatric Patient Plus Measles and Influenza Updates

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X Wang et al. N Engl J Med 2025;392:1334. Ménétrier’s Disease

  • History: 16-year-old girl was admitted to the hospital with a 2-month history of leg swelling and hypoalbuminemia. She had no gastrointestinal symptoms.
  • Treatment: She was placed on a high-protein diet and medications to eradicate a concurrent infection with Helicobacter pylori. At a 3-month follow-up visit, the patient’s edema and hypoalbuminemia had resolved.

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Measles as of Friday May 2nd (per Caitlin Rivers): “According to CDC, a total of 935 confirmed measles cases have been reported by 30 jurisdictions. The previous high was 1,274 in 2019. So far this year, 121 cases (13%) have been hospitalized.”

AP News May 2nd: CDC reports 216 child deaths this flu season, the most in 15 years

“More U.S. children have died this flu season than at any time since the swine flu pandemic 15 years ago, according to a federal report released Friday…It’s a startlingly high number, given that the flu season is still going on. The final pediatric death tally for the 2023-2024 flu season wasn’t counted until autumn…There are likely several contributors to this season’s severity, but a big one is that fewer children are getting flu shots, added O’Leary, a University of Colorado pediatric infectious diseases specialist. The flu vaccination rate for U.S. children has plummeted from about 64% five years ago to 49% this season. Flu vaccinations may not prevent people from coming down with symptoms, but research shows they are highly effective at preventing hospitalizations and deaths, O’Leary said.”

Long-Acting GLP-2 Analogue Glepaglutide Reduces Parenteral Support

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PB Jeppesen et al. Gastroenterol 2025; 168: 701-713. Open Access! Glepaglutide, a Long-Acting Glucagon-like Peptide-2 Analogue, Reduces Parenteral Support in Patients With Short Bowel Syndrome: A Phase 3 Randomized Controlled Trial

Background: “GLP-2 is a specific, endogenous, intestinal, pro-adaptive factor that plays a key role in enhancing intestinal mucosal morphology, function, and integrity under normal and pathophysiological conditions. The introduction of GLP-2 analogue treatment has been a paradigm shift in the treatment of SBS, targeting the pathophysiology of SBS by aiming to reinforce the structural and functional integrity of the remaining intestine. Exogenous GLP-2 induces significant hyperplasia of the small intestinal mucosal epithelium via stimulation of stem cell proliferation in the crypts and via inhibition of apoptosis in the villi…

The short half-life of 5–7 minutes for circulating native GLP-232 is a significant practical limitation for its use in a therapeutic setting. This is improved for the currently marketed GLP-2 analogue teduglutide, which has a half-life in circulation of approximately 2 hours.33 However, treatment is time-consuming due to the requirement for daily drug product reconstitution and dosing…

Glepaglutide is a novel, long-acting GLP-2 analogue in a stable, aqueous formulation for subcutaneous administration to treat patients with SBS. The stability in aqueous solution allows for dosing of glepaglutide as a ready-to-use liquid formulation. The mean effective half-life is 88 hours,34 which enables extension of the dosing interval beyond daily dosing.”

Methods: In this placebo-controlled, randomized, parallel-group, double-blind, phase 3 trial, adult patients (n=106) with SBS with intestinal failure requiring PS ≥3 d/wk were randomized 1:1:1 to 24 weeks of glepaglutide 10 mg twice weekly or once weekly or placebo

Key findings:

  • Glepaglutide twice weekly significantly reduced weekly PS volumes from baseline to week 24 vs placebo (mean change, −5.13 vs −2.85 L/wk; P = .0039; primary end point).
  • The improvement with glepaglutide was more prominent in those without a colon in continuity.
  • Mean concentrations of citrulline (a biomarker for enterocyte mass) increase 47% and 19% from baseline in the TW and OW treatment groups vs 5% in the placebo group
  • Serious adverse events were more common in both glepaglutide groups (28.6% and 11.4% for TW and OW respectively) compared to 5.6% for placebo. Specific risks of the active treatment included injection site reactions (common). Stoma complications (swelling of stoma nipple) along with GI events (nausea, vomiting and pain) were reported in more than 10% of patients. One patient developed cholecystitis and one developed a generalized rash in the active treatment group.
  • 61 of 70 patients (87%) treated with glepaglutide developed anti-drug antibodies. However, the authors found no apparent association with glepaglutide pharmacokinetics.
The improvement in parenteral support was more notable in those without the colon in continuity
Difference compared to placebo: 14.1% more of patients receiving twice weekly dosing and 11.2% more of patients receiving once weekly dosing of glepaglutide achieved enteral autonomy.

My take: This study shows that glepaglutide, like its GLP-2 analogue predecessor teduglutide, reduces the volume of parenteral support for patients with SBS. Due to its longer half-life, less frequent dosing is an added benefit compared to teduglutide.

Drawbacks for this group of medications include the potential for long-term adverse effects, endoscopic monitoring (possibly both upper endoscopy and colonoscopy), substantial costs, and reversion of intestinal failure severity when the medications are stopped.

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Elevated Fecal Calprotectin Levels in Pediatric Patients with H pylori Infection

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P Villalba-Davila et al. J Pediatr Gastroenterol Nutr. 2025;80:617–622 Helicobacter pylori infection is associated with significant elevations to fecal calprotectin, systemic inflammatory markers

In this retrospective study from a high immigrant density community, patients aged 6–18 years old who had an fecal calprotectin (FC) level within 6 months prior to EGD and who were tested for HP infection were included in the study. 

Key findings:

  • Of 129 patients, 37 (28.7%) tested positive for HP infection.
  • The mean FC level was significantly elevated in HP-positive patients (241.2) as compared with HP-negative patients (88.1) (p < 0.001)
  • HP-positive patients were also found to have small but notably higher elevations of CRP and ESR levels

My take: This study confirms what I have seen in my own practice. Patients with H pylori frequently have elevated calprotectin levels. Checking stool for H pylori may help avoid some colonoscopies. H pylori infection, however, can be present in patients with inflammatory bowel disease as well.

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Phang Nga Bay, Thailand

Celiac Disease: Lower TTG-IgA Titers Associated with Isolated Duodenal Bulb Presentation

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QY Wang et al. JPGN 2025; 80:678–685. Open Access! Low TTG-IgA associated with isolated bulb pathology in pediatric celiac disease: Implications in a no-biopsy approach era

Methods: There were 405 cases included in this retrospective study (mean age = 9.6 years). TTG-IgA values were considered negative if <4 U/mL, equivocal between 4 and 10 U/mL inclusively, and positive if >10 U/mL. At the authors’ institution, TTG‐IgA ≥10× ULN corresponds to ≥100 U/mL.

Key findings:

  • Bulb-restricted CD was present in 7.4% of cases
  • TTG-IgA was negative or equivocal in 60.0% of bulb-restricted CD, compared to 5.3% of distal duodenal CD (odds ratio [OR] = 26.6
  • No bulb-restricted CD cases attained TTG-IgA ≥10× ULN, compared to 48.5% of distal duodenal CD

My take: This study confirms and quantitates what most clinicians have experienced. Isolated duodenal bulb pathology is associated with lower celiac titer abnormalities.

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Gorgeous stained glass by Margaret Vetter at Piedmont Arts Festival

Bowel Obstruction in Newborn

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A Le-Nguyen. N Engl J Med 2025;392:1215. Meconium Ileus

An abdominal radiograph had shown dilated loops of small intestine (Panel A). Owing to concern for intestinal malrotation with midgut volvulus, an urgent laparotomy was performed. Considerable distention of the small bowel by thick meconium — rather than midgut volvulus — was identified. An enterotomy for evacuation of meconium was performed (Panel B). On postoperative genetic testing, the baby was found to be homozygous for a mutation in CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator… The condition is associated with a very high risk of cystic fibrosis, so genetic testing is warranted in all cases. Uncomplicated cases are typically managed with serial enemas. 

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Shingles Vaccine Linked to Lower Dementia Risk

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L Carroll. NBC News, 4/2/25: Shingles vaccine may protect against dementia, new study suggests

An excerpt:

It’s been shown that reactivation of the chickenpox virus can lead to the accumulation of aberrant proteins associated with Alzheimer’s…

The new research, published Wednesday in Nature, analyzed data from more than 280,000 older adults in Wales and found that people who received the original shingles live virus vaccine were 20% less likely to develop dementia of any type than those who were not vaccinated...

The new study was possible because of an unusual public health policy in Wales that provided a “natural experiment” to explore the potential impact of the vaccine on dementia risk. With the rollout of the vaccine on Sept. 1, 2013, in Wales, shots were offered to people who were 79 on that date but not given to people who had turned 80. That allowed the German and Stanford University researchers to compare two groups of people with similar health characteristics who differed only by one week in age...

Bolstering the case for the shingles vaccine protecting against dementia were the findings from a study published in Nature Medicine in 2024 that analyzed medical records from more than 100,000 patients. That analysis suggested the newer shingles vaccine was associated with even better protection against dementia.

Actual study:Eyting, M., Xie, M., Michalik, F. et al. . Nature (2025). https://doi.org/10.1038/s41586-025-08800-x Open Access! A natural experiment on the effect of herpes zoster vaccination on dementia

My take: Avoiding shingles is a great reason to get the vaccine. Lowering the risk of Alzheimer’s may convince more to take the shot.

For those wanting a deeper dive on this topic: Eric Topol, The Shingles Vaccine and Reduction of Dementia

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Ustekinumab in Pediatric Crohn’s Disease: Efficacy and Safety

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EB Mitchell et al. JPGN 2025;80:653–663. Ustekinumab is safe and effective in pediatric patients with Crohn’s disease

This was a retrospective longitudinal cohort study of 101 children with CD treated with ustekinumab from two large centers between 2015 and 2020. The median follow-up time on ustekinumab was 16.6 months. 

Key findings:

  • Fifty-nine patients were in steroid-free clinical remission at 1 year.
  • Higher baseline disease activity (odds ratio [OR]: 0.91 (p = 0.01) and stricturing/penetrating disease phenotype (OR: 0.14 p = 0.02) were associated with decreased likelihood of steroid-free clinical remission at 1-year
  • Ustekinumab drug escalation occurred in 70% of patients, and after escalation, 50 (70%) achieved clinical remission, and 49 (69%) achieved steroid-free remission at the last follow-up
  • Adverse events were rare and did not require therapy discontinuation

My take: More pediatric data showing efficacy for ustekinumab is important. My sense, though, is that newer IL-23 specific agents are going to eclipse ustekinumab in pediatrics as they are doing in adults.

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Genetic Advances in Congenital Diarrhea and Enteropathies (CODEs)

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Z Gaibee et al. N Engl J Med 2025;392:1297-1309. The Genetic Architecture of Congenital Diarrhea and Enteropathy

Background:”Congenital diarrhea and enteropathies (CODEs) are a group of rare disorders that primarily affect the function of intestinal epithelial cells, leading to infantile-onset diarrhea and poor growth. Molecular defects in CODEs can be classified into six categories: epithelial trafficking and polarity, immune-cell-regulation, nutrient and electrolyte transport, enteroendocrine-cell development, nutrient metabolism, and other. CODEs are associated with substantial morbidity and mortality. Patients often receive lifelong fluid and nutritional management. Genetic causes include pathogenic variants in MYO5B (microvillus inclusion disease), EPCAM (tufting enteropathy), NEUROG3 (enteric anendocrinosis), DGAT1 (protein-losing enteropathy), and SLC9A3 (congenital sodium diarrhea). Treatment options are currently limited. However, an understanding of some of the genetic causes of CODEs has led to targeted therapies such as dietary treatments and the development of preclinical pharmacologic treatments.”

Methods: In this case series with 129 infants, the authors  analyzed the exomes or genomes of infants with suspected monogenic congenital diarrheal disorders. Using cell and zebrafish models, we tested the effects of variants in newly implicated genes.

Key findings:

  • Causal genetic variants were identified in 62 infants (48%). This included a new founder NEUROG3 variant
  • Using cell and zebrafish models, the authors uncovered and functionally characterized three novel genes associated with CODEs: GRWD1, MYO1A, and MON1A

My take: Exome sequencing is an important part of the evaluation of infants with CODEs

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