Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:Primary sclerosing cholangitis (PSC) is characterised by substantial clinical heterogeneity. While normal gamma-glutamyl transferase (GGT) at one year predicts favourable outcomes, the heterogeneous trajectories underlying this remain uncharacterised. We applied latent class mixed modelling to identify distinct GGT trajectory phenotypes in paediatric PSC and evaluate their prognostic significance. METHODS:We analysed 782 children with PSC from the Pediatric PSC Consortium who had baseline GGT and at least one additional measurement over three years. Latent class mixed models were fit to log-transformed GGT values, with optimal model selection based on Bayesian Information Criterion and entropy. Cox proportional hazards models assessed associations between trajectory clusters and transplant-free survival, adjusting for baseline characteristics. We used multinomial logistic regression to assess whether cluster membership could be predicted using early markers. RESULTS:Four trajectory clusters were identified: persistently elevated (23%), moderate-stable (30%), elevated-declining (26%), and persistently low (21%). 5-year transplant-free survival differed markedly: 74%, 86%, 98%, and 96%, respectively (p<0.0001). The elevated-declining and moderate-stable clusters both had elevated baseline GGT but divergent outcomes, with the elevated-declining cluster achieving normalisation by year one. In adjusted analyses, persistently elevated and moderate-stable clusters had significantly higher transplant hazard versus persistently low (HR 6.45, 95% CI 2.87-14.5; HR 3.00, 95% CI 1.31-6.90). Transplant-free survival in the elevated-declining cluster was similar to the persistently low cluster (p=0.22). Favourable clusters had younger age with higher IBD prevalence. Cluster membership could be predicted using baseline and 6-month GGT values (AUC 0.83). CONCLUSIONS:GGT trajectory phenotypes identify clinically meaningful PSC subgroups with distinct prognoses. Early biochemical response, rather than baseline values alone, predicts long-term outcomes. IMPACT AND IMPLICATIONS/UNASSIGNED:Prognostic assessment in PSC has relied on cross-sectional biomarker measurements at single timepoints, limiting the ability to capture dynamic changes over time. By applying trajectory modelling to repeated GGT measurements in 782 children with PSC, we identified four distinct groups with significantly different transplant-free survival. Two clusters with similarly elevated baseline GGT followed divergent trajectories and had very different outcomes, information that cross-sectional assessment would miss. These trajectory phenotypes can be predicted using baseline and 6-month GGT values, offering clinicians an early tool to identify high-risk patients. Trajectory-based phenotyping may also facilitate clinical trial design by enabling patient enrichment strategies and providing an early surrogate endpoint.

Congenital bile acid synthesis defects (BASD), the most common of which is 3β-hydroxy-Δ5-C27-steroid dehydrogenase oxidoreductase (3β-HSD7) deficiency, are a rare cause of fat-soluble vitamin malabsorption. We describe a 14-year-old girl who presented at 14 months with a left distal femur fracture and failure to thrive. It was not until 13 years of age that after several hospitalizations for bleeding and severe vitamin K deficiency, the patient was ultimately diagnosed with 3β-HSD7 deficiency. We also describe the case of an adolescent girl who was referred for treatment of Hepatitis C (HCV) and diagnosed with 3β-HSD7 deficiency after she failed to respond to therapy as expected. Finally, we review the diagnosis of BASD and highlight the challenges involved in our clinical cases. These cases demonstrate the importance of maintaining a broad differential when evaluating any patient with unexplained fat-soluble vitamin deficiencies and represent unique presentations of 3β-HSD7 deficiency in adolescent patients.

The authors recognize the limitations of our study, most of which are due to being a single-center study and the small sample size of our cohort. We tried to keep our population as homogeneous as possible and included patients only with cirrhosis. Imaging modalities like cardiac MRI, 3D echocardiography, and tissue Doppler imaging as well as exercise testing often give us significantly more information about cardiac function but come with their inherent limitations of requiring general anesthesia, limited availability, and age-dependent variability. We agree with both reviewers that our study lacks the longitudinal aspect which would allow us to study the reversibility of findings post-liver transplantation. However, the purpose of our study was to correlate the pre-transplantation echocardiographic findings as a risk stratification method for post-transplantation clinical measures like duration of mechanical ventilation and length of hospital stay. We believe that the results of our study can serve as a basis for further prospective studies in the evaluation of patients prior to liver transplantation as well as demonstrating reversal of findings in long-term post-transplant period.

PURPOSE OF REVIEW/OBJECTIVE:To provide an update of recent advancements in pediatric hepatology, highlighting new diagnostic criteria, emerging therapeutic options, and molecular insights into liver diseases which are reshaping clinical practice and guiding future research. RECENT FINDINGS/RESULTS:Nonalcoholic fatty liver disease (NAFLD) has been redefned as metabolic dysfunction-associated steatotic liver disease (MASLD), reflecting an improved understanding of its underlying pathophysiology. Advances in immunophenotyping have identified activated T-cell hepatitis as a significant contributor to indeterminate pediatric acute liver failure. Additionally, the introduction of ileal bile acid transporter (IBAT) inhibitors marks a transformative shift in the management of pediatric cholestatic diseases including Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC), offering improved growth, quality of life, and native liver survival. SUMMARY/CONCLUSIONS:Recent developments in pediatric hepatology are changing how liver diseases are approached in clinical practice. Evolving disease classifications, expanded use of genetic and immunologic profiling, and the introduction of novel therapies mark a shift toward more individualized care. Ongoing research is needed to evaluate long-term outcomes and ensure that these advances translate into durable improvements for children with liver disease.

OBJECTIVES/OBJECTIVE:The trend of alanine aminotransferase (ALT), a biomarker of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease), remains poorly described for the pediatric population because no widely accepted cutoffs are available to categorize ALT value. We described the nuanced changes in the distribution of ALT continuous values. STUDY DESIGN/METHODS:We analyzed the data from 15,702 adolescents aged 12-19 who participated in the National Health and Nutrition Examination Surveys between 1988 and 2020. The ALT distributions were standardized for age and sex. The prevalence of elevated ALT was also assessed. RESULTS:percentile of the ALT distribution remained above 35 U/L by the end of the study period after jumping from 26.02 U/L in 1988-1994 to 33.83 U/L in 1999-2004. The prevalence of elevated ALT (>42 U/L in boys and 30 U/L in girls), doubled from 1.53% (0.87%-2.19%) in 1988-1994 to 3.49% (2.73%-4.25%) in 1999-2004, and lingered around 4% through 2020. CONCLUSIONS:The ALT mean decreased in recent years, but the prevalence of elevated ALT remained persistently high. Population-wide reductions in fructose consumption may have contributed to the decrease in ALT mean. The stagnant right end of the distribution, manifesting as the high prevalence of elevated ALT, calls for intensified clinical prevention.

Although cytomegalovirus (CMV) is a common complication after pediatric liver transplantation (PLT), the optimal method for CMV prevention is uncertain and lacks multi-centered investigation. We compared the effectiveness of short (<120d) versus long (>180d) CMV primary antiviral prophylaxis to prevent CMV disease in PLT, through a prospective cohort study of primary PLT (<18 yrs of age) recipients enrolled in the Society of Pediatric Liver Transplantation (SPLIT) registry from 2015 to 2019 with either donor or recipient CMV seropositivity. Participants were grouped into short or long prophylaxis based on their center's practice and intended duration. 199 PLT recipients were enrolled including 112 (56.3%) short and 87 (43.7%) long prophylaxis. End-organ disease was rare and similar between groups (2.7% and 1.1%; p=0.45). CMV DNAemia and syndrome were more common in the short compared to long (26.8% v. 13.8%; p=0.03 and 18.8% v. 6.9%; p=0.02). Neutropenia occurred more commonly with long prophylaxis (55.2% vs. 16.1%; p<0.001). Graft and patient survival were similar. Consideration of a short prophylaxis must weigh increased risk of CMV syndrome/DNAemia against medication burden and neutropenia of longer prophylaxis.

BACKGROUND:Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS:Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS:In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS:113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION:Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.

BACKGROUND:In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. 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 (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. 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 prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. FINDINGS/RESULTS:Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. INTERPRETATION/CONCLUSIONS:Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. FUNDING/BACKGROUND:Albireo Pharma, an Ipsen company.