Does a Liver Transplantation Improve the Course of Inflammatory Bowel Disease?

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AR Safarpour et al. Inflamm Bowel Dis 2023; 29: 973-985. Alterations in the Course of Inflammatory Bowel Disease Following Liver Transplantation: A Systematic Review and Meta-analysis

The authors identifed 25 studies which met inclusion criteria. Key findings:

  • In the analysis of studies with 3-category outcomes (n = 13), the pooled frequencies of patients (n=646) with improved, unchanged, or aggravated IBD course after LT were 29.4%, 51.4% (, and 25.2%.
  • Subgroup analyses revealed that patients with ulcerative colitis (UC), younger age at LT, or shorter duration of follow-up were more likely to have an improved disease course.
  • In the analysis of studies with 2-category outcomes (n = 12), the pooled frequencies of patients (n=672) with improved/unchanged or aggravated IBD course were 73.6% and 24.1%, respectively

My take: Despite the intensification of immunosuppression, most often the course of IBD is unchanged in patients following a liver transplantation.

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View from L’Jaardin Exotique in Eze, France

Why Didn’t Screening for Biliary Atresia Improve Outcome In This Study?

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ZJ Kastenberg et al J Pediatr 2023; 257: 113339. Fractionated Bilirubin Among 252 892 Utah Newborns with and Without Biliary Atresia: A 15-year Historical Birth Cohort Study

This retrospective study (2005-2019) used an administrative data from a large integrated healthcare network in Utah to identify newborns with abnormal fractionated bilirubins. since 2005, all newborns at this healthcare system had a fractionated bilirubin measured.

Key findings:

  • There were 252 892 newborns with fractionated bilirubin assessed, including 26 of those subsequently confirmed to have biliary atresia (BA).
  • Conjugated or direct bilirubin was elevated in all 26 infants with BA and an additional 3246 newborns (1.3%) without BA. The lowest direct bilirubin in the BA group was 0.6, just above cutoff value of 0.5 mg/dL. The conjugated bilirubin cutoff value wa 0.2 mg/dL.
  • The 15-year crude birth prevalence of BA was 0.68 per 10,000 births in this cohort
  • Median time to Kasai HPE was 69.5 days

This study found that all infants with BA have elevated conjugated or direct bilirubin at birth. The authors estimate that a healthcare system with about 30,000 deliveries per year, would have between 450 and 630 newborns that would require a second screen. In this group, 96 per 100,000 screened newborns (~1 in 1000) will have a positive second screen at 2-week well check and need further evaluation.

What I don’t understand about this paper is how the authors omit a discussion of the age of Kasai HPE. How is it that all of these newborns received a fractionated bilirubin and the age of Kasai HPE is not improved compared to other U.S locations that have not implemented universal testing? (Previous data from 15 ChiLDReN sites indicate age of Kasai HPE 65-70 days and unchanged over past 30 years, see blog post: Online Aspen Webinar (Part 5) -Biliary Atresia Diagnosis and Screening).

The authors note that implementation of screening could be improved with newer tests (eg. MMP-7) but that more analysis is needed to determine if screening is cost-effective and avoids harm (eg. subjecting healthy newborns to invasive testing).

My take: If universal screening is implemented, it is imperative to show that it helps and to set up the needed infrastructure to arrange appropriate followup. The first surrogate marker of this effort would be improving the age of surgical intervention.

As an aside, I find the new page numbering by The Journal of Pediatrics to be quite annoying. When you are going through the hard copy of the Journal, it is more difficult to find the articles that are listed in the table of contents because the articles are not ordered by lowest to highest numbered page. Each article is given a single page number like 113339 in this article but inside the article it is numbered page 1–10 (or however long the pages). The article prior could be a lower or higher page number. Until hard copies are eliminated, it would be an improvement if the articles could at least be ordered such that the next article would not have a lower page reference than the preceding article.

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Be Careful with Biliary Atresia Diagnostic Biomarkers

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B Aleiri et al. JPGN 2023; 77: 97-102. Matrix Metalloproteinase-7 and Osteopontin Serum Levels as Biomarkers for Biliary Atresia

In this study, serum was assessed from 32 biliary atresia (BA) patients and 27 controls.

Key findings:

  • Median MMP-7 was higher in BA (96.4 vs 35 ng/mL; P < 0.0001) with an optimal cut-off value of 69 ng/mL. Sensitivity and specificity was 68% and 93%, respectively [negative predictive value (NPV) = 71%]
  • Median osteopontin (OPN) was higher in BA (1952 vs 1457 ng/mL; P = 0.0001) and an optimal cut-off of 1611 ng/mL. Sensitivity and specificity was 84% and 78%, respectively (NPV = 81%)

The authors note that numerous studies from Asian countries have shown very high sensitivity and specificity for MMP-7. These studies used different cut-offs based on the testing kit. One limitation of this study was that samples were stored for a median of 12 years and perhaps this affected the results (some prior studies also used banked specimens).

My take: When these levels are very elevated, they are highly suggestive of BA. This study serves as a caution to note that the sensitivity at typical cut off values could be suboptimal

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Prevalence of Elevated ALT in U.S. Adolescents

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AK Mischel et al. JPGN 2023; 77: 103-109. Prevalence of Elevated ALT in Adolescents in the US 2011–2018

Using NHANES data for 12-19 year olds, the authors examined rates of elevated ALT. Elevated ALT was defined as >22 U/L (females) and >26 U/L (males)  Key findings:

  • Prevalence of elevated ALT in adolescents was 16.5% overall and 39.5% among those with obesity
  • For White (W), Hispanic (H), and Asian (A) adolescents, prevalence of elevated ALT was 15.8%, 21.8%, and 16.5% overall. In overweight adolescents, 12.8% (W), 17.7% (H), and 27.0% (A), and in those with obesity, 43.0% (W), 43.5% (H), and 43.1% (A) in those with obesity, respectively
  • Prevalence was much lower in Black adolescents (10.7% overall, 8.4% for overweight, 20.7% for obesity)
  • Prevalence of ALT at 2X-ULN was 6.6% in adolescents with obesity
  • Hispanic ethnicity, age, male sex, and higher BMI were independent predictors of elevated ALT

My take: It is hard to get very excited about a mildly elevated ALT value when 1 in 6 adolescents has this as well as ~40% of adolescents with obesity.

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Only 30% Ready for Transition from Pediatric IBD to Adult Practice

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A Foster et al. J Pediatr 2023; 258: 113403. Transition Readiness in Youth with Inflammatory Bowel Disease

In this cross-sectional multicenter study evaluating transition readiness in individuals (n=186, prospectively recruited ) with IBD 16-19 years old, the authors used the validated ON Taking Responsibility for Adolescent to Adult Care (ON TRAC) questionnaire. 

Key findings:

  • ON TRAC scores determined that 26.6% of AYAs at pediatric and 40.4% at adult centers reached the threshold of readiness. The findings are limited by potential nonresponse & sampling bias.
  • Disease remission negatively (P = .03) associated with ON TRAC scores.
  • A significant percentage of AYAs reported moderate-to-severe depression (21.7%) and generalized anxiety (36%); however, neither were significantly associated with ON TRAC scores

The authors suggest that a joint clinic with adult/pediatric providers may be helpful to improve transition.

MB Cohen. J Pediatr 2023; 258. DOI:https://doi.org/10.1016/j.jpeds.2023.113556 Are You Ready to Transition? In commentary on this article, Dr. Cohen writes the following: “a novel finding was that transition readiness was inversely related to disease remission; this confirms what had been previously suggested.1 Patients who are doing well may not be as engaged in developing skills for transition readiness and knowledge about their chronic illness, unlike those with more significant disease or symptoms.”

My take: Many studies show that adolescents and young adults with IBD are not fully prepared to transition to adult medical practices. In my view, it would be better to encourage the young adult to continue engaging with his/her parents until readiness is achieved rather than try to change to a multispecialty clinic.

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Infliximab Injections Coming Soon

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  1. L Gianolio et al JPGN 2023; 77(2):p 235-239, August 2023. Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy

Key findings: After switching from IV infliximab to SC 120 mg every other week, 6 of 7 patients remained in clinical remission with no significant changes in laboratory markers and median infliximab trough levels (12.3 µg/mL at baseline; 13.9 and 14.0 µg/mL at 6 and 40 weeks respectively). 

2. Gastroenterology & Endoscopy News (7/31/23) Safety, Efficacy of Subcutaneous Infliximab Supported by Trial

Excerpt:

In this multinational trial, called LIBERTY-CD, the median trough level was 16 mcg/mL, which is higher than that typically associated with IV dosing, according to Dr. Hanauer, who presented the results at Digestive Disease Week 2023 (abstract 1028)… “most professional societies to recommend a trough of 10 mcg/mL,” Dr. Hanauer said….

All patients received induction doses of infliximab by IV at weeks 0, 2 and 6. Those who achieved at least a 100-point reduction in the Crohn’s Disease Activity Index (CDAI), which accounted for 86% of the 396 patients initially enrolled, were randomized in a 2:1 ratio to receive 120 mg of subcutaneous infliximab (CT-P13) or placebo every two weeks.

The proportion of patients meeting the end point of clinical remission, defined on the basis of CDAI, was 62.3% for active therapy and 32.1% for placebo (P<0.0001). The proportion of patients in the active treatment arm achieving an endoscopic response was nearly three times higher than the proportion in the placebo arm (51.1% vs. 17.9%; P<0.0001).

My take: This study shows that SC infliximab (after IV induction) should be effective. A study showing that the SC product is not inferior to the IV dosing would be helpful. It is likely that vedolizumab will receive approval in U.S. for a similar IV induction followed by maintenance subcutaneous therapy in the next year.

Eze, France

High Rates of Denying Medical Care for Medicaid Patients Managed by Health Insurers

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7/19/23 NY Times: Insurers Deny Medical Care for the Poor at High Rates, Report Says

Some excerpts:

Private health insurance companies paid by Medicaid denied millions of requests for care for low-income Americans with little oversight from federal and state authorities, according to a new report by U.S. investigators published Wednesday.

Medicaid, the federal-state health insurance program for the poor that covers nearly 87 million people, contracts with companies to reimburse hospitals and doctors for treatment and to manage an individual’s medical care. About three-quarters of people enrolled in Medicaid receive health services through private companies, which are typically paid a fixed amount per patient rather than for each procedure or visit.

The report by the inspector general’s office of the U.S. Department of Health and Human Services details how often private insurance plans refused to approve treatment and how states handled the denials.

Doctors and hospitals have increasingly complained about what they consider to be endless paperwork and unjustified refusals of care by the insurers when they fail to authorize costly procedures or medicines…The investigators also raised concerns about the payment structure that provides lump sums per patient. They worried it would encourage some insurers to maximize their profits by denying medical care and access to services for the poor...

The investigators emphasized the insurers were much more aggressive in refusing to authorize care under Medicaid than under Medicare…Unlike with Medicare, if an insurer refuses to authorize a treatment, patients are not automatically provided with an outside medical opinion as part of their appeal...

The investigators also found that state oversight of coverage denials was lax. Many states do not routinely examine the insurers’ denials nor collect information about how many times a plan denies requests for prior authorization...

The denial rates recorded by the investigators varied widely by insurer and by state.

My take: This is more evidence of the distorted incentives in U.S. healthcare where health insurance companies profit when patients are denied beneficial care.

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Comparative Efficacy: Infliximab vs. Ustekinumab

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ECL Wong et al. Inflamm Bowel Dis 2023; 29: 1015-1023. Open Access! Comparative Efficacy of Infliximab vs Ustekinumab for Maintenance of Clinical Response in Biologic Naïve Crohn’s Disease

This post hoc analysis included data from separate trials examined the response of 220 biologic-naïve CD participants to either inflximab biosimilar or ustekinumab.

Key findings:

  • Clinical remission: One-year clinical remission (CR) and corticosteroid-free CR rates were similar between infliximab-treated and ustekinumab-treated patients (CR, 66 of 110 [60.0%] vs 63 of 110 [57.3%]; adjusted odds ratio [aOR], 1.15), corticosteroid-free CR, 11 of 28 (39.3%) vs 27 of 51 [52.9%]; aOR, 0.58)
  • Endoscopic response/remission:  infliximab-treated participants were more likely to achieve 1-year endoscopic response (43 of 92 [46.7%] vs 6 of 30 [20.0%], aOR, 3.59) and endoscopic remission (31 of 92 [33.7%] vs 4 of 30 [13.3%]; aOR, 3.35)

In the discussion, the authors note only 1 head-to-head study in CD with ustekinumab. “The SEAVUE trial (NCT03464136) compared adalimumab and ustekinumab among biologic-naïve CD patients. Ustekinumab demonstrated similar efficacy for the achievement of clinical and endoscopic outcomes compared with adalimumab.23 Similar rates of CR at 1 year were reported in SEAVUE (64.9% ustekinumab vs 61% adalimumab) as in our analysis (57.3% ustekinumab vs 60% infliximab)…ustekinumab demonstrated longer retention and lower immunogenicity and has practical advantages over adalimumab, including less frequent dosing intervals (every 8 weeks for ustekinumab vs every 2 weeks for adalimumab) while providing similar efficacy.”

My take: This study suggests that infliximab may be a little better than ustekimumab in biologic-naive patients due to the higher endoscopic response; however, the study was unpowered to provide a definitive answer. A prior study suggested similar endoscopic healing rates (P Riviere et al. Inflamm Bowel Dis 2023; 29: 923-931).

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What I Don’t Like About a “Multidisciplinary Approach” for Infants with GERD-Like Symptoms

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MH Fishbein et al. JPGN 2023; 77: 39-46. A Multidisciplinary Approach to Infants With GERD-Like Symptoms: A New Paradigm

This was a retrospective study (2011-2019) with 174 full-term infants (<6 months of age). The physician in the study decided which infants needed evaluation by SLP and/or OT.

Key findings:

  • “GERD-like symptoms” were present in 109 with 46 having concerns for dysphagia, 37 having colic/unsettledness, and 26 with concerns combined for dysphagia/colic. 65 were determined to have uncomplicated GER.

The authors conclude that “a multidisciplinary approach, including SLP and OT, is recommended for the evaluation of infants with GERD-like symptoms.” Of note, all but one of the authors are either OTs or SLPs. The authors also promote their AAP book: The CALM Baby Method: Solutions for Fussy Days and Sleepless Nights as a resource for pediatricians and families

Here’s what I don’t like about the recommendations:

  • If taken literally, the authors essentially advocate that a huge percentage of infants need to be seen by OT and SLP as many infants have GERD-like symptoms. The authors cite a review that indicated that 10-25% of infants have GERD symptoms at 1 month; however, other studies have found much higher numbers.
  • While this article stresses the fact that medications are not helpful for GERD symptoms and the importance of not overlooking dysphagia, in my experience many SLPs and OTs are frequently advocating for infants to be placed on GERD medications. In addition, many SLPs and OTs attribute a variety of infant (non-reflux) behaviors to GERD.
  • In many infants with dysphagia, the clinical evaluation by SLP does not have a high sensitivity due to silent aspiration. As such, SLP involvement could be focused on those with objective evidence of dysphagia.

My take: Most infants with GERD-like symptoms do not need to be seen by SLPs or OTs. Dysphagia symptoms (eg. choking, cough with eating, stridor, congestion, poor feeding) need to be evaluated.

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Population-Based Study: Prevalence of Bowel and Bladder Dysfunction in Early Childhood (Good Bowel Control is Happening Later)

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SJ Verkuijl et al. JPGN 2023; 77: 47-54. Open Access! The Prevalence of Bowel and Bladder Function During Early Childhood: A Population-Based Study

Methods: This cross-sectional questionnaire study (n=791 Dutch children) up to age 7 yrs of age.

Key findings:

  • The mean age at which parents/caregivers considered their child fully toilet-trained was 5.1 ± 1.5 years. “Compared to studies performed 15 years ago, we found toilet training to be completed at an older age (23,26–28).”
  • Prevalence of fecal incontinence among toilet-trained children was 12%.
  • Prevalence of constipation was 14%, with excessive stool retention (75.9%) and painful/hard stools (78.7%) as the 2 most common symptoms.
  • The prevalence of urinary incontinence among all toilet-trained children was 40%. The majority of these urinary incontinent children suffered from daytime incontinence (56%). Enuresis occurred in 22% and the other 22% suffered from combined daytime incontinence and enuresis.
  • There were significant associations between fecal incontinence and constipation [odds ratio (OR) = 3.88], fecal incontinence and urinary incontinence (OR = 5.26), and constipation and urinary incontinence (OR = 2.06)
  • Half of the children with constipation and almost all the children with fecal incontinence remained untreated.
Stool Frequency by age (Figure 1 B)

In the discussion, the authors note “treatment of constipation and/or fecal incontinence often leads to the resolution of urinary incontinence (34).”

In my experience, many families sent by urologists have been told that the constipation is causing urinary incontinence. For many children, the explanation is more complicated; association of constipation does not indicate causation. A lot of children have limited sensation of response to both bowel and bladder, rather than the rectum pushing on the bladder. Most children that I see with constipation/encopresis do not have urinary incontinence. However, behavior approaches to toileting can be helpful for both.

My take: This is a useful study providing an updated view on when to expect good toileting and highlighting the frequency of bowel/bladder dysfunction (which is often untreated).

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