Highlights
– Condition-specific weight-for-age and height-for-age charts for children with Alagille syndrome (ALGS) were generated from 1204 children using generalized additive models for location, scale and shape (GAMLSS), and differ substantially from US CDC charts.
– Estimated median adult heights on ALGS-specific charts are reduced compared with CDC curves (boys: ~171.5 cm vs 176 cm; girls: ~156.5 cm vs 163 cm).
– The ASSERT phase 3 randomized trial found that odevixibat (120 μg/kg/day) significantly improved caregiver-reported pruritus and reduced serum bile acids over 24 weeks versus placebo, with manageable safety profile.
Background and clinical need
Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder most commonly caused by pathogenic variants in JAG1 or, less frequently, NOTCH2. The phenotype includes intrahepatic bile duct paucity with chronic cholestasis, characteristic cardiac defects, vertebral anomalies, ocular findings, and dysmorphic facies. Cholestasis in ALGS frequently begins in infancy and is associated with fat-soluble vitamin deficiencies, failure to thrive, severe pruritus, and in some patients progression to end-stage liver disease requiring transplantation.
Routine clinical care typically relies on normative growth references such as CDC or WHO charts to evaluate nutrition and growth failure. For uncommon, syndromic disorders that affect linear growth and weight trajectories, use of standard charts can misclassify nutritional status and influence high-stakes decisions such as timing of listing for liver transplantation. Separately, pruritus and elevated serum bile acids are major drivers of morbidity in ALGS; effective targeted medical therapies that reduce bile acids and itch could change management and potentially nutritional status.
Study designs
Condition-specific growth charts (GALA study)
This international multicenter case series leveraged data assembled by the Global Alagille Alliance (GALA) between May 14, 2018 and March 20, 2023. Inclusion criteria for growth-chart construction were full-term births (Jan 1, 1997 to Aug 31, 2019) with a clinically and/or genetically confirmed diagnosis of ALGS and the native liver. Children with documented prematurity were excluded from chart development. The analytic approach used generalized additive models for location, scale and shape (GAMLSS) to derive percentile curves for weight-for-age and height-for-age for boys and girls, and compared these to US CDC growth charts to illustrate differences in growth patterns.
ASSERT: randomized trial of odevixibat
ASSERT was a phase 3, double-blind, randomized, placebo-controlled trial conducted at 21 centers in ten countries. Eligible patients had genetically confirmed ALGS, significant pruritus, and elevated serum bile acids. Participants were randomized 2:1 to odevixibat 120 μg/kg/day orally or placebo for 24 weeks, stratified by age (<10 years vs ≥10 to <18 years). The primary efficacy endpoint was change in caregiver-reported scratching score (PRUCISION instrument, 0–4) from baseline to weeks 21–24. A prespecified key secondary endpoint was change in serum bile acid concentration averaged over weeks 20 and 24. Analyses included all patients who received at least one dose of study drug (full analysis set).
Key findings
Growth charts — cohort and outcomes
The growth-chart analysis included data from 1204 children in the weight cohort (695 boys; 9855 weight observations) and 1106 children in the height cohort (635 boys; 8464 height observations). Median gestational age was 38 weeks. Most children (≈82%) had a history of neonatal cholestasis; around one-quarter underwent liver transplantation during follow-up (25.4% in weight cohort; 25.9% in height cohort); mortality in the cohorts was 7.8–8.1%.
Median birth weights were 2.8 kg (IQR 2.5–3.0) for boys and 2.6 kg (IQR 2.4–2.9) for girls; median birth lengths were 48.0 cm (IQR 46.0–50.0) for boys and 47.0 cm (IQR 45.0–49.0) for girls. The derived weight-for-age and height-for-age percentile curves for boys and girls with ALGS differed markedly from CDC charts across childhood. On the ALGS-specific curves the estimated height at age 18 years corresponding to the 50th percentile was 171.5 cm for boys and 156.5 cm for girls, compared with 176 cm and 163 cm respectively on CDC charts — illustrating a systematic downward shift in linear growth.
Clinical implications: Use of condition-specific charts may alter nutritional classification, timing of interventions (caloric supplementation, enteral feeding), and assessments used when prioritizing children for liver transplantation. Standard charts can overestimate failure relative to an ALGS-specific reference and may therefore either inappropriately trigger evaluations/interventions or, conversely, mask pathological growth if syndrome-specific baselines are not considered.
ASSERT — efficacy and safety results
Fifty-two patients were randomized (35 odevixibat, 17 placebo); median age was 5.5 years, and sex distribution was balanced. Baseline mean caregiver-reported scratching scores were elevated (2.8 for odevixibat; 3.0 for placebo).
At weeks 21–24 the mean scratching score decreased to 1.1 (SD 0.9) with odevixibat versus 2.2 (SD 1.0) with placebo. Least-squares mean change from baseline was −1.7 (95% CI −2.0 to −1.3) for odevixibat and −0.8 (95% CI −1.3 to −0.3) for placebo; the between-group difference in LS mean change was −0.9 (95% CI −1.4 to −0.3), p=0.0024 — a clinically meaningful improvement in pruritus reported by caregivers.
For serum bile acids, mean baseline concentrations were high (≈237 μmol/L for odevixibat and 246 μmol/L for placebo). At the average of weeks 20 and 24 mean concentrations fell to 149 μmol/L with odevixibat versus 271 μmol/L with placebo. The LS mean change difference was −113 μmol/L (95% CI −179 to −47), p=0.0012, indicating a robust biochemical effect consistent with the drug’s mechanism.
Safety: The most frequent treatment-emergent adverse event with odevixibat was diarrhoea (29% vs 6% placebo); febrile illness rates were similar. Seven patients experienced serious adverse events (five in odevixibat arm, two in placebo); no patient discontinued treatment and there were no deaths during the 24-week randomized period. The overall safety profile was manageable in this pediatric population.
Interpretation and clinical implications
Together these studies address two complementary needs in ALGS care: accurate growth assessment and non-surgical symptom control. Condition-specific growth charts provide tailored reference data that can refine nutritional assessment, guide timing of enteral support, and inform transplant-listing deliberations. Because ALGS has a characteristic pattern of linear growth attenuation, transplant centers and pediatric hepatology programs should consider integrating condition-specific references into their workflows to reduce misclassification and support shared decision-making.
ASSERT demonstrates that pharmacologic inhibition of the ileal bile acid transporter (IBAT) with odevixibat reduces enterohepatic bile acid recirculation, lowers serum bile acids, and produces clinically important reductions in caregiver-reported pruritus over 24 weeks. For children with ALGS in whom pruritus contributes to sleep disruption, poor intake, and impaired quality of life, odevixibat may offer a non-surgical therapeutic option that complements nutritional and supportive care and could, in principle, improve growth trajectories indirectly by reducing pruritus-related feeding disturbances.
Limitations and areas for further research
Growth-chart limitations include cohort composition and generalizability: although large for a rare disease, the GALA cohorts reflect international referral patterns that may under- or over-represent specific ethnic groups, socioeconomic strata, or severity phenotypes. Charts were developed using data from children born full-term; their applicability to children born preterm is limited. Longitudinal effects of interventions (medical therapy, transplantation) on growth trajectories require prospective evaluation.
ASSERT’s strengths include randomized, double-blind design and clinically relevant endpoints, but the trial was relatively small (n=52) with 24-week duration. Longer-term follow-up (ASSERT-EXT and other extension studies) is needed to assess sustained efficacy, growth and nutritional outcomes, effects on progression to transplantation, and rare safety events. Whether reductions in serum bile acids and itch translate into improved growth, quality of life, or delayed need for transplantation remains to be established.
Expert commentary
These advances are complementary: condition-specific growth curves give clinicians a more realistic baseline against which to measure response to interventions, while odevixibat provides a targeted tool to address a symptom (pruritus) that can interfere with intake and sleep. Multidisciplinary teams — pediatric hepatology, nutrition, transplant surgery, and genetics — should integrate these data into patient counseling and management plans. Registries and prospective studies linking medication use, biochemical response, pruritus scores, and longitudinal growth will help determine whether medical bile-acid reduction modifies long-term outcomes in ALGS.
Conclusion
Condition-specific growth charts and the ASSERT randomized trial together advance care for children with Alagille syndrome. Syndrome-specific growth references will improve the accuracy of nutritional assessment and decision-making about transplant candidacy. Odevixibat provides evidence-based medical therapy to reduce pruritus and serum bile acids in children with ALGS, with an acceptable short-term safety profile. Future work should evaluate whether improved symptom control translates into better growth, delayed transplantation, and improved long-term health.
Funding and trial registration
ASSERT was funded by Albireo Pharma, an Ipsen company. The ASSERT trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28). The growth-chart work used data from the international Global Alagille Alliance (GALA) study.
References
1. Huysentruyt K, Vandriel SM, Roelants M, et al; Global Alagille Alliance (GALA) Study Group. Condition-Specific Growth Charts for Children With Alagille Syndrome. JAMA Netw Open. 2025 Nov 3;8(11):e2545294. doi: 10.1001/jamanetworkopen.2025.45294. PMID: 41284294; PMCID: PMC12645329.
2. Ovchinsky N, Aumar M, Baker A, et al. Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2024 Jul;9(7):632-645. doi: 10.1016/S2468-1253(24)00074-8. Epub 2024 Apr 23. PMID: 38670135.
AI thumbnail prompt
A pediatric hepatologist at a clinic desk reviewing tablet-displayed growth percentile curves while a toddler with jaundice and worried parents sits nearby; overlay of stylized bile-acid molecules and a small medication bottle labeled “Odevixibat”; soft clinical lighting, realistic, empathetic tone.
