Title: Impacts of Alagille syndrome on sleep of patients and their caregivers 

Source: Sleep Medicine 2026, Feb 13. [E–publication]

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Date of publication: February 2026

Publication type: Article 

Abstract: Aim: Alagille syndrome (ALGS) is a rare multisystem genetic disorder characterized by cholestatic liver disease, severe pruritus, and various systemic abnormalities. Sleep disturbances are a significant aspect of the disease burden. This study investigated sleep habits and disturbances in children with ALGS and their caregivers.

Methods: The Children’s Sleep Habits Questionnaire (CSHQ) and the Sleep Disturbance Scale for Children (SDSC) were administered to 13 children with ALGS and compared with age- and sex-matched controls (N = 13; total sample = 26), while the Pittsburgh Sleep Quality Index (PSQI) was applied to assess caregivers’ sleep quality.

Results: Children with ALGS showed substantial medical, functional, and sleep-related burdens. Total scores in the ALGS group on both questionnaires indicated broad sleep dysfunction, which was not influenced by transplantation status, medication type, or neurodivergence. Compared with controls, ALGS children demonstrated significantly higher CSHQ scores for sleep duration, night wakings, and parasomnias, as well as elevated SDSC scores for disorders of initiating and maintaining sleep and sleep-wake transition disorders. Correlation analyses revealed that several child sleep disturbances, including night wakings, daytime sleepiness, sleep-related anxiety, and disordered breathing, were associated with poorer caregiver sleep, underscoring interconnected sleep disruption within families.

Conclusion: This study shows that children with Alagille syndrome experience marked and multifactorial sleep disturbances that extend beyond cholestatic pruritus. Caregivers also demonstrated impaired sleep quality, highlighting the bidirectional impact of ALGS on family well-being. These findings underscore the need for integrated management strategies. Future work should incorporate objective sleep measures, longitudinal assessment of pruritus and treatment responses to develop ALGS-specific sleep interventions.

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Title: Efficacy of ileal bile acid transport inhibitors in children with Alagille syndrome: a meta-analysis

Source: European Journal of Pediatrics 2025, 184 (12): 737 

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Date of publication: November 2025

Publication type: Meta analysis

Abstract: Cholestatic pruritus is a debilitating and treatment-resistant symptom in children with Alagille syndrome (ALGS), impairing sleep, psychosocial functioning, and quality of life. Current therapies are limited. Ileal bile acid transport inhibitors (IBATIs) are a novel therapeutic option, but evidence remains fragmented. This study aimed to assess the efficacy and safety of IBATIs (maralixibat and odevixibat) versus placebo in pediatric ALGS. Data sources from PubMed, EMBASE, and the Cochrane databases were searched up to November 30, 2024. Randomized placebo-controlled trials enrolling children with genetically or clinically confirmed ALGS and reporting validated pruritus or sBA outcomes were eligible. Two reviewers independently extracted data on design, participants, interventions, outcomes, and adverse events. The risk of bias was assessed using RoB2, and the certainty of evidence was evaluated with GRADE. Four RCTs including 138 children (mean age 6.1 years; 54% male) were analyzed. IBATIs reduced pruritus severity (SMD – 1.00; 95% CI – 1.64 to – 0.35), lowered sBA levels (MD – 91.09 µmol/L; 95% CI – 136.11 to – 46.06; P < .0001), and improved PedsQL scores (MD 10.13 points; 95% CI 4.88 to 15.39). Transient ALT elevations were observed; gastrointestinal events were common, but mild and self-limiting. The limitations of this study include heterogeneity in pruritus measures and dosing, short follow-up (≤ 24 weeks), and the use of non-interchangeable pruritus instruments across trials, requiring SMD pooling and precluding between-drug comparisons.

Conclusion: IBATIs are effective and well tolerated in pediatric ALGS, providing meaningful improvements in pruritus and quality of life. Longer trials are needed to confirm durability, safety, and transplant-free survival impact.

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Title: Therapeutic approach to genetically-determined cholestatic liver diseases in paediatric and adult patients

Source: Digestive and Liver Disease 2025, Dec 2. [E–publication]

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Date of publication: December 2025 

Publication type: Article

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Title: Condition-specific growth charts for children with Alagille syndrome  

Source: JAMA Network Open 2025, 8 (11): e2545294

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Date of publication: November 2025  

Publication type: Article

Abstract: Importance: Different degrees of growth delay have been reported in children with Alagille syndrome (ALGS), yet these patients are routinely evaluated using standard growth charts.

Objective: To develop condition-specific growth charts for ALGS using modern statistical approaches.

Design, setting, and participants: This case series used data from the international, multicenter Global Alagille Alliance (GALA) study accrued between May 14, 2018, and March 20, 2023. Children born at full term between January 1, 1997, and August 31, 2019, with a clinically and/or genetically confirmed ALGS diagnosis and their native liver were included. Data from children with a known history of prematurity were excluded for the development of the growth charts. Data were analyzed from March 25, 2023, to December 30, 2024.

Exposure: Growth of children with Alagille syndrome.

Main outcomes and measures: Generalized additive models for location scale and shape were fitted to generate percentile plots for weight and height relative to age and superimposed on US Centers for Disease Control and Prevention (CDC) growth charts to illustrate differences in growth patterns compared with children with typical development.

Results: Data from 1204 children with ALGS in overlapping cohorts (median [IQR] gestational age, 38 [37-39] weeks) were analyzed (1204 in the weight cohort; 695 boys [57.7%]; 9855 weight observations; 995 with neonatal cholestasis [82.6%]; 306 receiving a liver transplant [25.4%]; 98 deaths [8.1%] and 1106 in the height cohort, 635 boys [57.4%]; 8464 height observations; 906 with neonatal cholestasis [81.9%]; 287 receiving a liver transplant [25.9%]; 86 deaths [7.8%]) were included for the modeling of the weight-for-age and height-for-age charts, respectively. The median birth weight was 2.8 kg (IQR, 2.5-3.0 kg) for boys and 2.6 kg (IQR, 2.4-2.9 kg) for girls. The median birth length was 48.0 cm (IQR, 46.0-50.0 cm) for boys and 47.0 cm (IQR, 45.0-49.0 cm) for girls. The weight-for-age and height-for-age growth charts for boys and girls with AGLS differed significantly from CDC growth charts. The estimated height at age 18 years corresponded to the 50th percentile was 171.5 cm for boys and 156.5 cm for girls on the condition-specific charts vs 176 cm and 163 cm, respectively, on the CDC growth charts.

Conclusions and relevance: These findings suggest that condition-specific growth charts for ALGS may provide a crucial tool for clinicians to evaluate growth and aid in decision-making around listing children for liver transplant.

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Title: Elevated serum bile acids predict poor liver outcomes in children with Alagille syndrome: results from the GALA study group

Source: Liver International 2025, 45 (12): e70423

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Date of publication: November 2025

Publication type: Cohort study

Abstract: Background and aim: Alagille syndrome (ALGS) is a rare disorder characterised by cholestasis and extrahepatic manifestations. Given the current era of ileal bile acid transporter (IBAT) inhibitor therapies that reduce serum bile acid (SBA) levels, we evaluated whether SBA predicts liver disease outcomes in ALGS.

Methods: Patients were ascertained from the Global ALagille Alliance (GALA) cohort. A prognostic threshold of SBA 102 μmol/L was assessed as a time-dependent covariate in Cox regression analyses for native liver survival (NLS) and event-free survival (EFS), while adjusting for total bilirubin (TB) levels.

Results: 570 GALA patients were included (348 [61%] male). There was a moderate positive correlation between SBA and TB (Pearson correlation = 0.47, p < 0.001). SBA below 102 μmol/L was a significant predictor of outcomes (NLS: HR = 3.78, 95% CI 2.39-5.99, p < 0.001; EFS: HR = 3.44, 95% CI 2.35-5.04, p < 0.001). SBA remained a significant predictor for improved EFS after adjusting for TB clearance at 1 year (TB < 2 mg/dL; HR = 2.00, 95% CI 1.10-3.65, p = 0.02). Median SBA in the first year of life above 102 μmol/L, predicted lower NLS (67.2% vs. 83.5% at 7 years p = 0.05) and EFS (63.4% vs. 80.9% at 7 years, p = 0.02).

Conclusion: Lower SBA in children with ALGS liver disease predicts improved NLS and EFS. SBA is also associated with NLS in children with ALGS who clear their bilirubin, that is, those with anicteric cholestasis. Although the patients studied here did not receive IBAT inhibition, these data suggest that lowering SBA may improve important clinical outcomes.

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Title: An overview of paediatric autoimmune and genetic cholestatic liver disease for the adult physician 

Source: Clinical Medicine 2025, Nov 19. [E–publication]

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Date of publication: November 2025

Publication type: Review article

Abstract: Paediatric chronic liver diseases are rare but are increasingly encountered in adult practice as survival improves and more adolescents transition to adult services. Adult physicians must be familiar with these conditions, recognise complications and implement high-quality management of these conditions to provide safe, effective care. Autoimmune liver disease in children includes autoimmune hepatitis, autoimmune sclerosing cholangitis and primary sclerosing cholangitis, with distinct serological and clinical profiles. Cholestatic disorders such as progressive familial intrahepatic cholestasis and Alagille syndrome present additional challenges, often impacting multiple organs and requiring multidisciplinary care. Many patients will enter adulthood having undergone liver transplant, requiring long-term immunosuppression and, where relevant, family planning advice. Recognition of extra-hepatic manifestations, metabolic complications and mental health issues is essential to holistic management. This article outlines the key paediatric liver diseases relevant to adult practice, highlighting key elements of care and long-term considerations for this unique and often complex patient population.

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Title: Prospective multicenter longitudinal measurement of liver stiffness in school-age children with cholestatic liver disease

Source: Gastro Hep Advances 2025, 4 (10): 100788 

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Date of publication: September 2025

Publication type: Multicenter prospective longitudinal study

Abstract: Background and aims: A multicenter prospective longitudinal study of vibration-controlled transient elastography (VCTE) in school-age children with biliary atresia (BA), alpha-1 antitrypsin deficiency (a1-AT) and Alagille syndrome (ALGS) was undertaken to test the hypothesis that there would be measurable disease progression over 2 years.

Methods: Vibration-controlled transient elastography was performed annually for 2 years in children with BA, a1-AT and ALGS.

Results: Valid liver stiffness measurement (LSM) was determined at baseline/second follow-up in 254/180 (71%), 104/58 (56%) and 100/61 (61%) participants (mean elapsed time 2.27 years) with BA, a1-AT and ALGS, respectively. Modeling did not reveal a relationship between LSM and time since baseline: BA 1.2% (-1.6, 4.2%), a1-AT 0.1% (-3.8, 4.2%), and ALGS 3.6% (-2.9, 10.5%) LSM (% change/year; mean [95% confidence interval]). Similarly, mean LSM did not change significantly from baseline to visit 2 (BA 13.6 + 11.0 vs 15.1 + 12.8; a1-AT 7.8 + 5.1 vs 8.5 + 7.6; ALGS 10.6 + 9.4 vs 12.2 + 12.1 kPa, mean + standard deviation). Albumin and total bilirubin levels did not change in these participants. Platelet counts dropped at rates that were similar to a national representative sample, the National Health and Nutrition Examination Survey (ie, 5000 to 7000/μL per year).

Conclusion: Surprisingly, longitudinal measurement of LSM and laboratory parameters of liver disease severity over 2 years in school-age children with compensated BA, a1-AT, and ALGS did not reveal significant change, consistent with slow progression of cholestatic liver disease in this age group. These findings have implications for both clinical care and interventional trials in this patient population.

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Title: Plasma proteome correlations with liver stiffness in pediatric cholestasis implicate epithelial to mesenchymal transition 

Source: Hepatology Communications 2025, 9 (10): e0796

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Date of publication: September 2025  

Publication type: Article

Abstract: Background: Pediatric cholestatic liver diseases can be characterized by rapidly progressive fibrosis. A multicenter cross-sectional analysis of vibration-controlled elastography in biliary atresia (BA), alpha-1 antitrypsin deficiency (A1AT), and Alagille syndrome (ALGS) was leveraged to interrogate the plasma proteome relative to liver stiffness measurements (LSM).

Methods: Slow off-rate modified aptamer scanning profiling of >7000 proteins in plasma from 187 children with BA (n=93), A1AT (n=31), ALGS (n=46), and healthy pediatric controls (n=17) was performed, and correlations with LSM were undertaken.

Results: There was an abundance of LSM correlated proteins (BA n=2720, A1AT n=694, ALGS n=5968). Interestingly, a distinct plasma proteome was found in ALGS relative to BA and A1AT. Weighted Correlation Network Analysis identified groups of proteins with strong LSM correlation (eg, in a BA module of interest, Pearson correlation coefficient 0.79, p=5´0-21). Machine learning developed models predicting LSM as a continuous variable (median R2=0.62 for BA). For BA, time to transplant could be predicted equally well by the proteome or clinical parameters (elastic net models achieved a C-index using proteome 0.91, clinical parameters 0.91, proteome and clinical parameters 0.90). Single-cell transcriptomics predicted the potential hepatic cell of origin for the most informative proteins, which included macrophage, mesenchymal, mesothelial, and endothelial cells. The epithelial-to-mesenchymal transition pathway was enriched in LSM correlated proteins in all 3 diseases.

Conclusions: The plasma proteome is highly correlated in a disease-specific fashion with LSM in BA, A1AT, and ALGS. These correlations provide unique opportunities to identify biomarkers and focus attention on epithelial-to-mesenchymal transition in pediatric cholestasis.

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Title: Ileal bile acid transporter inhibitors in alagille syndrome and progressive familial intrahepatic cholestasis: a systematic review into dose-response

Source: British Journal of Clinical Pharmacology 2025, Sep 30. [E–publication]

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Date of publication: September 2025

Publication type: Systematic review 

Abstract: Ileal bile acid transporter inhibitors (IBATi), including maralixibat and odevixibat, are a novel approach to the treatment of paediatric cholestatic liver diseases, such as Alagille syndrome (ALGS) and different forms of progressive familial intrahepatic cholestasis (PFIC). Multiple phase 3 trials have demonstrated efficacy of IBATi in alleviating pruritus and decreasing serum bile acid (sBA) in a significant subset of patients. While most clinical IBATi trials included low-dose and high-dose treatment, a consistent dose-response effect has not been uniformly reported. This systematic review aims to assess the dose-response relationship for IBATi in patients with ALGS or PFIC, based on available pruritus, sBA and (non-)responder outcomes, identifying minimally effective dosage and exploring the potential for personalized dosing strategies. A systematic search was conducted across PubMed, EMBASE, Web of Science and Cochrane Library of articles, oral presentations, posters presentations and abstracts up to 29 July 2024. The analysis included 75 records, of which 68 reported sBA and 63 reported pruritus outcomes. An evident dose-response relationship was not observed for either maralixibat or odevixibat in PFIC or ALGS. In the case of odevixibat, outcomes measures for patients with ALGS have only been reported for a dosage of 120 μg/kg/day. In conclusion, the variability in therapeutic outcomes of different doses for all IBATi underscores the necessity for personalization of dosing, which may include decreasing the dosage for responders to IBATi.

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Title: Diagnostic approaches for infants with cholestatic liver diseases: Position paper and perspectives of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition

Source: Journal of Pediatric Gastroenterology and Nutrition 2025, Sep 22. [E–publication]

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Date of publication: September 2025

Publication type: Position Paper

Abstract: Cholestasis in infancy is the most common manifestation of liver disease in children, with some patients progressing to cirrhosis or liver failure necessitating transplantation. Neonatal cholestasis remains a diagnostic challenge, as it requires differentiation of cholestatic infants from a large number of jaundiced newborns with benign causes. The first step is to diagnose patients with biliary atresia (BA) as early as possible to ensure timely surgery-Kasai portoenterostomy (KPE). Universal newborn screening using stool color cards or direct bilirubin measurements have been shown to identify patients before the onset of symptoms. Multiple diagnostic modalities, including clinical history, physical examination, laboratory tests, emerging biomarkers, imaging studies, and liver histopathology, can facilitate the decision for intraoperative cholangiography and potential corrective surgery. Advances in diagnostic testing, particularly genetic sequencing, have greatly enhanced our ability to evaluate and manage infants with cholestasis. Given highly variable resources and access to these new diagnostic modalities, local flexibility and adaptability should be implemented within each institution and medical care system to foster seamless collaboration between primary care physicians and specialized centers with expertise in genetic diagnosis, KPE, and liver transplantation. This report provides updates on the evaluation of neonatal cholestasis, including insights into screening, diagnosis, and genetic testing, along with future perspectives.

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