Methods: In this single-center, observational study, the authors deployed an anonymized survey of outcomes that was completed by 107 parents of children with BA who were younger than age 12 years. A detailed assessment of general neurodevelopment (Mullens Scale of Early Learning and Vineland Adaptive Behavior Scale) was carried out in 50 infants younger than 5 years old, and emerging autistic traits (Autism Diagnostic Observation Schedule) were assessed in those eligible. There were 93 matched controls.
Key findings:
Neurodevelopmental concerns were raised by 37% of parents
47% of children required support from at least 1 service (such as speech and language therapy physiotherapy, play therapy, or seen a clinical psychologist), and a further 42% (n = 45) had used more than 1 service. The most accessed service was speech and language therapy (20%, n = 10)
A clinical or research diagnosis of autism was made in 30% of 35 children >2 years old
Early surgical intervention and faster clearance of jaundice after surgery was associated with better general neurodevelopmental outcomes (F = 2.428, P = .042) but not with the presence of emerging autistic traits
My take: High levels of neurodevelopmental difficulties occur in children with BA.
Background: After the START trial in 2014, it seemed that enthusiasm for post-operative steroids for biliary atresia had waned. The START study did not find that steroids improved outcomes after Kasai hepatoportoenterostomy (HPE). Subsequently, though, there have been observational reports of using steroids in a customized fashion to improve outcomes. Langreen et al add to this literature by examining their use of rectal budesonide (2 mg) for 3 months in a retrospective cohort (n=142) with a historical control (n=137). Jaundice-free native liver survival (jfNLS) was assessed at 6 months, 2 years, 5 years, and 10 years post-Kasai.
Key findings:
Improvements were noted in jfNLS at 6 months (53% vs. 39%) , 2 years (45% vs. 22%), 5 years (40% vs. 23%) and 10 years (32% vs. 13%)
These benefits were exclusive to patients with nonsyndromic BA
No serious adverse effects were identified with budesonide
Rationale for rectal budesonide: The authors note that “a single dose of budesonide foam contains about 2 mg of budesonide, equivalent to 25 mg of prednisolone or 20 mg of methylprednisolone…In our series, no serious steroid associated adverse effects were recorded, possibly due to the first pass after rectal administration.”
Limitations: “The retrospective nature of our data analysis allows for variability in the follow‐up protocols, potential biases (historical control group, change of surgeons) and confounding factors cannot be entirely ruled out.”
Kaplan–Meier curve comparing native liver survival between the study and control groups over a 10‐year follow‐up.. Study group—blue. Control group—orange.
My take: The START study with 140 participants was well-designed and did not find a benefit with systemic steroids. However small differences in outcomes can be difficult to identify. Rectal budesonide may improve outcomes. A randomized, double-blind, placebo-controlled trial would be more definitive.
Recently Dr. Balistreri gave our group an excellent lecture. I have taken some notes and shared some slides. There may be inadvertent omissions and mistakes in my notes.
Key Points:
Producing enough bile acids and recycling bile acids in enterohepatic circulation is crucial for bile acid flow. In addition, there are ‘good’ bile acids like cholic acid that have trophic properties and ‘bad’ bile acids like lithocholic acid that cause liver toxicity
In addition to defects in the metabolic pathway of bile acids, discoveries identified defects in the membrane transporters (eg. FIC1, BSEP, MDR3), trafficking proteins (eg. MYO5B, VPS33B), nuclear control receptors (eg. FXR), and tight junction proteins (eg. TJP2). Tight junction protein defects are associated with bile leakage from bile canaliculus
Alagille syndrome, a disorder of embryogenesis, related to JAG1-NOTCH2 signaling pathways affects organs throughout the body
Many of these genetic mutations are now being identified in adults with unexplained liver diseases (eg. intrahepatic cholestasis of pregnancy and cryptogenic cirrhosis)
Cholestasis panels and whole exome sequencing are important tools
Ileal bile acid transporter (IBAT) inhibitors have emerged as important therapies for conditions like Alagille which were previously treated with biliary diversion
My take: This lecture really shows how the field of pediatric liver disease has been a puzzle. Now one can see how almost all of the pieces of the puzzle work together.
This is a useful review summarizing advances in the management of cholestatic diseases.
Treatment with IBAT inhibitors:
“Improvement in both pruritus and serum BAs/bilirubin levels has been associated with improved event‐free survival and 6‐year transplant‐free survival in ALGS patients treated with maralixibat. Additionally, this class of medication improved overall growth of the patient by improving mean height and weight Z scores that may be related to reduced impact of high serum bile acid levels on the growth axis although further studies are needed to better define the mechanism responsible for this out-come. This finding suggests these parameters could be used as surrogate end‐points for disease severity in diseases like ALGS or PFIC, where the time course to develop the need for LT commonly occurs over many years.”
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.
Methods: MMP-7 was measured in serum samples of 399 infants (North America)18 with cholestasis in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p = 0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved fluorescence energy transfer assays.
Key findings:
On the single-plex assay, MMP-7 generated an AUROC of 0.90. At cutoff 52.8 ng/mL, it produced sensitivity = 94.03%, specificity = 77.78%, positive predictive value = 64.46%, and negative predictive value = 96.82% for BA.
MMP-7 outperformed other parameters. AUROC for gamma-glutamyl transferase = 0.81 (CI: 0.77–0.86), stool color = 0.68 (CI: 0.63–0.73), and pathology = 0.84 (CI: 0.76–0.91). Obstructive features on pathology were the second-best predictor of BA.
GGT cutoff was 267.5 U/L (per personal communication with senior author) with sensitivity of 86.6%, and specificity of 77.4%
Similar results were found with TR-FRET assay with cut-off of 18.2 ng/mL.
6% (False-negatives) of BA patients had MMP-7 levels below the cutoff
22% (False-positives) of non-BA patients had MMP-7 levels above the cutoff. This included 7 of 8 choledochal cyst patients, 8 of 17 with A1AT, and 13 of 98 with indeterminate cholestasis
In the discussion, the authors note that MMP-7 has performed better in studies with Asian populations, MMP-7 could be useful for dried blood spots in newborns, and could be useful as a measure of successful HPE; continued elevation of MMP-7 has been associated with hepatic fibrosis.
My take: This study shows that MMP-7 is not a perfect assay but often quite helpful. The exact cutoff depends on the specific assay that is utilized. Also, this study shows that checking for A1AT and checking an ultrasound to exclude choledochal cyst need to continue to be done early in the evaluation process.
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.
F Koutny et al. JPGN 2024;https://doi.org/10.1002/jpn3.12194. Open Access! Poorly controlled pediatric type 1 diabetes mellitus is a risk factor for metabolic dysfunction associated steatotic liver disease (MASLD): An observational study
Study population, n=32,325. Key finding: Inadequately controlled T1D (HgbA1c >11%) was associated with a higher hazard ratio ((HR: 1.54) of elevated ALT values compared to children with controlled T1D over an observation period extending up to 5.5 years. When both elevated HbA1c (>11%) and overweight were present, the HR was 2.71.
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2. G Indolfi et al.JPGN 2024;78:957–972. ESPGHAN recommendations on treatment of chronic hepatitis C virus infection in adolescents and children including those living in resource-limited settings
Summary of Recommendations:
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3. F Lacaille et al. JPGN 2024; 78:1374–1382. Awareness, referral and age at Kasai surgery for biliary atresia in Europe: A survey of the Quality-of-Care Task Force of ESPGHAN
Key finding: Data from 785 infants diagnosed with BA from 2015 to 2019 from 18 centers in 15 countries revealed a mean age at referral to tertiary center of 55 days (similar to results obtained in Europe 10–30 years earlier)
This single center retrospective study compared 20 consecutive infants underwent hepatoportoenterostomy (HPE) (beginning in 2017) for biliary atresia (BA) to a historical cohort. Analysis of successful biliary drainage 3 months after HPE (defined as serum total bilirubin (TB) <2 mg/dL) was the primary endpoint; survival with native liver at 2 years was the secondary endpoint.
Protocol:
Cefoxitin was administered to all infants following HPE for 3-4 days.
Standard protocol: If the stool color normalized (pigmented), the infant received “conventional” treatment with trimethoprim-sulfamethoxazole cholangitis prophylaxis, fat-soluble vitamin supplementation with DEKAsPlus or AquaADEKs (1 mL daily), and ursodeoxycholic acid (5 mg/kg twice daily).
Customized protocol: If the stools were acholic (or not consistently pigmented) and </=45 days, the infants received intravenous cefoxitin or piperacillin-tazobactam and methylprednisolone, initial dose 5 mg/kg/day and decreased by 1 mg/kg/day each day thru day 5; then orally treated with dose dropped 0.25 mg/kg weekly. When switched to oral steroids, IV antibiotics were stopped and infant was placed on amoxicillin-clavulanate which was continued until TB <2 mg/dL or discontinuation of corticosteroids (whichever came first).
If stools were acholic and infant was >45 days, then the same treatment was given if there was liver inflammation on histology.
Key findings:
8 had pigmented stools after HPE and received standard protocol.
12 had acholic/inconsistent stools. All of those >45 days had liver inflammation; thus, all 12 received the customized protocol. Two infants had two cycles of steroids/antibiotics who had initial response to treatment and then worsened.
Sixteen of 20 (80%) infants had successful bile drainage, compared to 8 of 20 (40%) infants in the historical cohort (P = 0.0225)
Among the sixteen who have reached two years of age, 11 (68.8%) are alive with native livers versus 10 of 20 (50%) in the historical cohort (P = 0.0970). This did not achieve statistical significance.
The authors established their protocol based on data from Kings College in 2016 suggesting that steroids appeared effective in younger patients who underwent HPE prior to 45 days (Peg Surg Int 2016; 32: 193-200). The START study showed no significant improvement in biliary drainage between patients receiving corticosteroids and placebo. However, in the group <70 days, 72% of infants receiving corticosteroids achieved biliary drainage compared with 57% of the placebo group (P=0.36).
My take: This is a small sample size. Perhaps, this protocol will help improve outcomes. If so, we still don’t know which factor is more important —the IV antibiotics or the high dose steroids. If these agents are helpful, are there other predictive factors –microbiome? MMP-&?
START Study: Steroids Not Effective For Biliary Atresia (After Kasai) In this study, the steroid intervention did not affect transplant-free survival which was 58.7% in the steroid group and 59.4% in the placebo group at 24 months of age. In addition, steroids were associated with an earlier onset of first serious adverse events.
This retrospective study analyzed data from 11,965 infants who had fractionated bilirubin obtained in the nursery (2016-2019). Key findings:
DB of 0.6 mg/dL was chosen as the cut-off based on a high sensitivity (100%) and specificity (99%) for screening newborns for CLD
Out of 60 infants who met criteria for DB ≥0.6 mg/dL, only 15 (25%) had a repeat level drawn after nursery discharge; 3 (5%) were eventually diagnosed with CLD (2 with BA and 1 with Alagille syndrome)
It is fairly easy to get fractionated bilirubins on infants. Many need to get a bilirubin check and in many centers, a fractionated bilirubin is automatically generated at no additional costs. The hard part is making sure that those with abnormal values receive timely followup.
My take: It is a mistake to get fractionated bilirubins in newborns unless one has developed a plan/infrastructure to make sure those with abnormal values receive appropriate followup.
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.
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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