The burden of Alagille syndrome: uncovering the potential of emerging therapeutics – a comprehensive systematic literature review

Seventy-seven epidemiology studies were considered for full text review. Throughout these studies, themes associated with patient population, mortality, pathogenesis and natural history, native liver survival and diagnosis were explored. No studies that reported prevalence or incidence rates met the inclusion criteria for the literature review.

The clinical diagnostic criteria for ALGS include bile duct paucity on liver histology (classed as a bile duct to hepatic artery ratio of <0.5) as well as at least three out of the seven typical clinical symptoms: cholestasis, characteristic facial features, vertebral abnormalities, eye abnormalities, heart defects, skeletal abnormalities, kidney abnormalities and vascular abnormalities [2]. Genotyping can be used as confirmatory testing for the diagnosis; a JAG1 variant has been shown to be present in 86% to 98% of cases and a NOTCH2 variant present in 2–5% of cases [18,19,20,21]. In an analysis by Vandriel et al. [21] using the Global Alagille Alliance (GALA) registry, the largest natural history registry assessing outcomes in >1600 patients with ALGS, 755 JAG1 and 19 NOTCH2 patients were identified. Patients with the NOTCH2 variant were significantly less likely to have ALGS characteristic facies, a cardiac anomaly confirmed by echocardiography, or butterfly vertebrae. However, the incidence of neonatal cholestasis, bile duct paucity and renal anomalies, as well as overall survival rates, were similar between JAG1 and NOTCH2 patients with ALGS.

Cholestasis is a hallmark symptom of ALGS [9]. In a retrospective study evaluating the symptomology of patients with ALGS, 82.9% of patients had chronic cholestasis identified between birth and 24 months of age [22]. Furthermore, of the 37 patients undergoing liver biopsy, 32 had a paucity of intrahepatic bile ducts [22]. Another study included 32 children with cholestasis (median age: 8 years), 13 of whom had paucity of interlobular bile ducts as well as three or more criteria of ALGS [23].

Cardiovascular, ophthalmologic, renal, skeletal anomalies and dysmorphic anomalies are the major diagnostic criteria outside of liver manifestations, with peripheral pulmonic stenosis, butterfly vertebrae and ocular posterior embryotoxon noted as other diagnostic features [24]. Synonymous syndromic features of ALGS were also reported in other studies, together with cholestasis and systolic cardiac murmurs [25,26]. Kohaut et al. [27] observed in their cohort of patients with ALGS who received a liver transplant that all of the children had at least three disease-specific features, and almost half of them (26 of 55) presented with all clinical features. Genetic testing was also performed in these patients; however, it is unclear whether the genetic testing predated the observation of the clinical features of ALGS or vice versa.

ALGS is a heterogeneous condition, characterized by a variety of clinical manifestations, which inform diagnosis but also define progression of disease. Ninety-five percent of children will develop issues with the liver, of which 85% will have neonatal onset of cholestasis [10]. Debilitating pruritus secondary to cholestatic liver disease manifests in 74% of patients at a median age of 12 months. Cardiovascular abnormalities are quite common in patients with ALGS [28,29]. Structural cardiac abnormalities, like tetralogy of Fallot, are associated with significant morbidity and mortality in patients with ALGS, with the highest mortality rate (75%) reported in patients presenting with both tetralogy of Fallot and pulmonary atresia; the mortality rate in patients with tetralogy of Fallot alone is 34% [12]. Renal abnormalities have been reported to occur in 19–74% of patients with ALGS [1]. Importantly, a study evaluating patients from a North American liver transplantation database indicated that patients with ALGS who have preexisting renal insufficiency may potentially worsen following liver transplantation [8]. Children are often born with clear skeletal abnormalities, which are the typical clinical manifestations clinicians will diagnose at birth. Patients with ALGS are predisposed to poor bone heath, including osteoporosis and metabolic bone disease, which is related to malabsorption and fat-soluble vitamin deficiencies [30,31] and is associated with increased fracture risk [32]. Thus, it is not surprising that children with ALGS have smaller bones and lower bone mass compared with their age group peers, which might explain the observed differences in stature [33].

As children with ALGS age, morbidity develops beyond liver manifestations, with 28% of patients experiencing xanthomas, macular atrophy and progressive vision loss [34,35,36]. Development of neurodevelopmental disorders may affect IQ, and 84% of patients will experience significant cardiac disease, some of which may restrict their ability to be able to receive a liver transplant [37].

Lack of physical development further impacts a child's ability to thrive and keep up with peers. Failure to thrive issues fundamentally impact a child's growth, characterized by smaller bones, weaker joints and reduced growth and height compared with their peers that does not necessarily catch up after liver transplant [33,38,39]. Children with ALGS may continue to experience these growth disparities even after liver transplant.

Extensive disease burden, characterized by the wide variety of clinical manifestations, leads to collateral mortality issues. Patients who had liver dysfunction and received congenital heart surgery before or instead of liver transplantation reportedly had a fourfold higher relative risk of mortality compared with those without liver dysfunction [40]. The risk of death for those who did not receive a liver transplant at 5, 10 and 18 years was 6.1, 7.8 and 9.3%, respectively. Patients who underwent surgical biliary diversion experienced a 1.9-fold increase in risk of liver transplant/death. Overall, native liver survival to early adulthood ranges between 20 and 40% [10,19]. Patients can also develop manifestations in adulthood. Li et al. reported diagnosis in adults of cholestasis, butterfly vertebrae, systolic murmurs and typical facies in 50, 62, 12.5 and 12.5% of patients, respectively [26]. In 5 epidemiology studies, the reported overall survival (OS) rates were between 80.4 and 92.9% among patients with ALGS, regardless of liver transplantation status [21,27,41,42,43]. The reported 10-year and 18-year OS rates were 92.9 and 90.7%, respectively, whereas reported native liver survival rates were substantially lower than OS – 69.7 and 56.5%, respectively [21,43].

Management of liver disease in ALGS focuses on controlling the symptoms of pruritus and providing nutrition to help alleviate fat-soluble vitamin deficiencies [1]. While several clinical management approaches have been employed for pruritus associated with ALGS, they are often insufficient [44]. Prior to the development and approval of IBAT inhibitors for the treatment of cholestatic pruritus in ALGS, the management of pruritus has been largely supportive, with choleretic agents (ursodeoxycholic acid [UDCA]) and other medications (cholestyramine, rifampicin, naltrexone) used to address the itch [2,44,45]. However, the efficacy of these agents is limited, and many have intolerable adverse event (AE) profiles [46]. Pruritus is often refractory to treatment with established therapies and is a leading indication for liver transplantation as indicated previously [12,44,45,47,48].

Cholestatic pruritus in ALGS is sometimes managed by surgically interrupting the enterohepatic circulation of bile acids through partial biliary diversion [44,49,50]. The long-term efficacy of such interventions is a matter of debate, and the risk associated with surgery, as well as the medical and psychosocial burden related to a permanent stoma, warrants careful consideration [1,51,52,53]. Due to disease management shortcomings for ALGS, liver transplantation is often performed and associated with complications.

Main indications for liver transplantation in patients with ALGS are persistent cholestasis including intractable pruritus, growth failure, xanthomas, metabolic bone disease, and/or fat- soluble vitamin deficiency [10]. Native liver function may deteriorate due to cholestasis-induced cirrhosis in patients with ALGS, leading to liver failure [24]. It has been reported that by 5 years of age, 15–30% of children with ALGS will progress to advanced liver disease requiring liver transplant [15].

Liver transplantation brings substantial mortality risk to children. Between 20 and 75% of patients will require a liver transplant by 18 years of age, with the median age of liver transplant reported at 2.8 years [10]. Of those, 72% of transplantations are expected to occur in patients below the age of 6 years [54]. Most patients will expect a longer hospital stay due to complications associated with ALGS, compared with similar liver indications [39,55]. Survival rates post-liver transplant at 5, 10 and 20 years were reported as 92, 91 and 88%, respectively [10].

The LOGIC study, a longitudinal study of liver disease progression in patients, including those with ALGS (n = 293), reported that only 24% of patients with ALGS survive to early adulthood (95% CI: 16–36%) with their native liver, reflecting the high rate of liver-related complications [30]. Among 11 patients who died with native liver during the study, only three of these deaths were directly attributable to liver disease.

These data are supported by findings from the GALA study, indicating survival with native liver was 40.3% at 18 years of age [34]. The probability of survival to 20 years of age has been reported as 80% in patients with ALGS who did not require liver transplant and the predicted probability of survival to 20 years of age in all patients is 75%, indicating that liver involvement has a major impact on long-term morbidity and mortality [25]. Another analysis of the GALA data by Habash et al. [56] reported a previously unrecognized substantial liver disease burden, with 95% of all the patients having liver involvement at any given time and 85% having neonatal cholestasis. Furthermore, survival with native liver was reported as 51% at 10 years and 38.5% at 20 years [11]. Overall, the impact on native liver survival depends on the degree of cholestasis in infancy, as demonstrated by data from GALA.

Black et al. reported that children with ALGS were more likely to receive a diagnosis of congenital heart disease (80.7 vs 16.4%; p < 0.001) as compared with children with other forms of liver disease, which increases potential complications with liver transplantation [55]. Forty (25.6%) children with ALGS required some type of cardiac intervention (catheter or surgical) either before or after successful liver transplantation, with 19 (12.2%) of them receiving more than one intervention.

Kamath et al. 2reported that 70% of children with ALGS required liver transplantation by 17 years of age, of which 10% died (3 deaths were liver related) [19]. The mean age of patients receiving liver transplantation was between 5 and 6 years of age (range: 1–17 years) [12,27,57]. Another study reported that death occurred after liver transplantation in 5 of 12 patients, of which all 5 deaths were caused by transplant complications [29]. In the LOGIC trial, 58 participants received liver transplants and 11 died with native liver in the study follow-up [30]. Data from the Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) 2022 Annual Report indicated that posttransplant mortality among all pediatric liver transplant recipients irrespective of indication was 4% at 6 months, 6% at 1 year, 8.2% at 3 years, 9.8% at 5 years and 13.9% at 10 years [58].

A total of 10 HRQoL publications were identified in the literature review reporting outcomes using the Pediatric Quality of Life Inventory (PedsQL), Family Impact Scale (FIS), Multidimensional Fatigue (MF) Scale Score and Child Health Questionnaire – Parent Form 50 (CHQ-PF50) in patients with ALGS (Table 1). There were no studies that reported utilities or disutilities associated with ALGS management. Burden is defined as the impact of living with ALGS, measured by cost, mortality and other factors. A single publication reported on financial burden.

Elisofon et al. [47] reported CHQ-PF50 outcomes; children with ALGS who did not undergo a liver transplant had significantly lower HRQoL, as measured by physical summary scores, than patients who received liver transplants due to any liver disease (43.06 vs 48.1, respectively; p < 0.05). While there have been no comparisons of the CHQ-PF50 between children with ALGS and healthy children, variations of this questionnaire have been studied in healthy children in Europe and the US and have demonstrated markedly higher HRQoL values than what are observed in the aforementioned study in children with ALGS either with or without a liver transplant [59,60,61].

Kamath et al. [62] demonstrated significant impairments in HRQoL in patients with ALGS compared with healthy patients (determination of ‘healthy’ was based on parent/caregiver reporting [63]) using the PedsQL, which is a 0 to 100 scale with higher values associated with improved HRQoL. In this study, lower scores were reported in the ALGS cohort compared with healthy patients: 69.86 ± 16.09 versus 83.91 ± 12.47, respectively.

Quadrado et al. [64] examined changes in PedsQL items over time by using mixed-methods approach to create vignettes using ALGS clinical trial data. The utility scores obtained in this study demonstrate the wide-ranging negative impact of ALGS symptoms on patients' and caregivers' quality of life (QoL) for each of four different health states–progressive cholestasis, non-progressive cholestasis, after a successful liver transplant and chronic transplant failure.

Quadrado et al. [65] highlighted the significant HRQoL burden faced by caregivers of children with ALGS, with a focus specifically on work, economic burden, sleep quality and emotional well-being, with liver transplant status having an effect on each parameter. All children who did not receive a liver transplant reported debilitating pruritus. Compared with caregivers of children with moderate or severe pruritus, caregivers of children with no pruritus or mild pruritus had significantly better sleep quality (p = 0.008). Most caregivers (79%) reported a negative financial impact from caregiving. Fifty-nine percent changed employment due to their caregiving role and 18% of all caregivers had stopped working entirely. Caregivers of individuals who had not received a liver transplant had markedly higher anxiety scores compared with those who had received a liver transplant and marginally higher depression scores, as measured by the Hospital Anxiety and Depression Scale (HADS). Posttraumatic stress has been reported in caregivers of children following liver transplantation in similar indications. Changes in work productivity, leading to economic issues, as well as an impact on sleep and relationships, were also reported [66].

Menon et al. [15] demonstrated the burden of ALGS-associated pruritus, which interrupts sleep, resulting in poor scholastic performance and causes lichenification of skin and secondary infections.

Elisofon et al. [47] reported the one study to date that has explored the impact on caregivers for patients with ALGS. In a comparison of proxy Child Health Questionnaire scores between parents of children with ALGS versus those with attention-deficit/hyperactivity disorder and juvenile rheumatoid arthritis, ALGS caregivers had significantly increased impairment (p ≤ 0.5) in psychosocial subdomain scales, including limited parental time, stress and worry and interruption of family activities.

Taken together, these studies highlight the significant impairment in HRQoL, physical health and psychosocial functioning of patients with ALGS and the negative emotional impact and burden this has on their caregivers and family.

Two publications reported cost and resource use in patients with ALGS.

Miloh et al. [16] reported the cost and resource use in 53 commercially insured and 100 Medicaid-insured children who received a liver transplant, noting that for both populations, the majority of costs incurred were due to inpatient visits. Ebel et al. [70] reported similar findings in their cost and resource use publication, which assessed 171 commercially insured and 215 Medicaid-insured patients with ALGS. Costs reported in Miloh et al. [16] were higher (commercial: $512,124 vs $57,029; Medicaid: $211,863 vs $24,820), as reported amounts were for high-cost liver transplants, whereas Ebel et al. [70] reported cost and resource use for general healthcare visits in the ALGS population. While the costs were higher in the Miloh et al. study due to the focus on patients who received a liver transplant, in the Ebel et al. analysis, a total of 14 patients (11 Medicaid-insured and 3 commercially insured) also received a liver transplant during the follow-up period. The annualized mean total medical costs for patients with liver transplants were markedly higher compared with those without a liver transplant, irrespective of commercial or Medicaid insurance (commercial: $387,197 [liver transplant] vs $51,097 [no liver transplant]; Medicaid: $92,226 [liver transplant] vs $21,185 [no liver transplant]). The wide ranges of costs and resource uses among patients with ALGS suggest a lack of standardized treatment regimens for patients and highlight the impact of liver transplants on medical costs.

Table 2 captures annualized costs from both studies and demonstrates the economic burden of cholestatic liver disease. With such high per-patient costs, it could be suggested that future treatment mitigating some of the key complications for patients could be cost-effective in addition to improving QoL.

A total of 27 clinical references were identified as having measured the efficacy and safety of treatments for cholestatic pruritus associated with ALGS. Table 3 summarizes the key clinical studies identified in the literature review and Table 4 summarizes the results of the outcomes of these papers. Appendix E contains the additional clinical studies identified and their outcomes.

As mentioned, prior to September 2021, treatment options available for patients with ALGS were mainly used for supportive or symptomatic relief. They included off-label use of UDCA to increase bile flow and other medications to help manage pruritus [71]. However, the evidence clearly indicated that these interventions are not very effective, and the majority of patients do not respond or combination therapy is required, which is associated with a number of issues as well [46]. Given that patients with ALGS have intrahepatic accumulations of bile acids that damage the liver and have additional deleterious multisystemic effects, developing therapies that focus on interrupting the enterohepatic circulation and reducing the bile acid pool are key [72,73].

Due to its key role in bile acid reuptake, the IBAT inhibitor is a rational target for pharmacologic interruption of bile acid recirculation [74,75]. IBATs are responsible for the reabsorption of about 95% of intestinal bile acids [76]. Inhibition of IBATs results in a reduction in bile acid reabsorption, which is associated with an increase in the levels of bile acids excreted in the feces and a decrease in the levels of bile acids returning to the liver [77,78].

Maralixibat is a novel oral IBAT inhibitor with minimal systemic absorption and is the first medication approved to treat cholestatic pruritus in patients with ALGS ≥3 months of age in the US and ≥2 months of age in the EU [79,80]. It is also approved for the treatment of cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (PFIC) ≥12 months of age in the US and for the treatment of PFIC in patients ≥3 months of age in the EU [79,80].

Gonzales et al. reported the findings from the pivotal ICONIC trial [13]. The ICONIC trial was a placebo-controlled, randomized withdrawal, phase 2b study with an open-label extension in children (aged 1–18 years) with ALGS. The ICONIC trial had 3 prespecified periods in the core study: (1) an open-label run-in period from baseline to Week 18; (2) a 4-week double-blind, placebo-controlled randomized withdrawal period (RWD) from Weeks 19 to 22, in which all patients were randomly assigned to remain on maralixibat or receive placebo; and (3) an open-label period from Weeks 23 to 48. After the core study, participants had the option of continuing into the open-label extension. Data out to 204 weeks were discussed in the manuscript.

In ICONIC, the primary efficacy end point was the mean change in serum bile acid (sBA) levels during the RWD in participants who previously achieved an sBA reduction from baseline to Week 12 or 18 that was met through treatment with maralixibat. There were significant differences in sBA between the maralixibat group and the placebo group during the RWD (mean difference, -114 μmol/l; p < 0.05), with sBA levels of those in the placebo group returned to levels similar to baseline values. Once all participants had resumed treatment with maralixibat, significant sBA reduction was observed from baseline to Week 48 and maintained up to Week 204 (-181 μmol/l vs baseline; p < 0.05). These findings demonstrate the long-term efficacy of maralixibat in decreasing sBA levels.

For cholestatic pruritus, measured by Itch-Reported Outcome (Observer) (ItchRO[Obs]), a significant improvement was seen from baseline to Week 18 (ItchRO[Obs], -1.7 [p < 0.05]). During the RWD, the effect was maintained in the maralixibat group, but not in the placebo group, with statistical significance demonstrated between the two groups. In the first 48 weeks, 84% of participants had a ≥1-point decrease (clinically meaningful improvement) in their ItchRO(Obs) score at least once. The results for the Clinician Scratch Scale (CSS) were consistent with those for ItchRO(Obs), demonstrating the efficacy of maralixibat in decreasing cholestatic pruritus.

A significant correlation between decreasing sBA and ItchRO(Obs), as reported in ICONIC, demonstrated the causal relationship between the two key clinical markers [13,81].

Shneider et al. presented the impact of maralixibat on sBA levels from a pooled analysis (n = 57) of 4 maralixibat clinical studies (ITCH [NCT02057692], IMAGO [NCT01903460], IMAGINE [NCT02047318, long-term follow-up of IMAGO] and IMAGINE-II [NCT02117713, long-term follow-up of ITCH]) [82]. The results showed a -80 μmol/l change from baseline sBA to Week 48. In addition, Kamath et al. reported that mean height Z-scores significantly increased from baseline to Week 204 in patients with an sBA response (<200 μmol/l) at Week 48 (p = 0.0013). There was no significant change in height Z-scores among patients with sBA ≥200 μmol/l [83].

Safety findings from Gonzales et al. 2021a [13] and Shneider et al. [82] demonstrated that long-term maralixibat usage was generally well tolerated, with the most common AEs being diarrhea, vomiting and abdominal pain. These events were mild to moderate in severity and transient in nature, with most occurring within the first 4 weeks of treatment and resolving within 1 week.

Odevixibat is an IBAT inhibitor that was recently approved for the treatment of cholestatic pruritus in patients with ALGS ≥12 months of age in the US and is also approved for the treatment of pruritus in patients with PFIC ≥3 months of age in the US and ≥6 months of age in the EU [86,87]. Ovchinsky et al. [88,89,90] evaluated the efficacy and safety of odevixibat in patients with ALGS (n = 52) in the pivotal, phase III, double-blind, randomized, placebo-controlled ASSERT clinical trial. The core trial was 24 weeks in duration with an option to enroll in the open-label extension (ASSERT-EXT). The primary pruritus end point was change in scratching from baseline to month 6 (Weeks 21–24), as measured by the PRUCISION observer-reported outcome (ObsRO) caregiver instrument. Pruritus was significantly improved with odevixibat (120 μg/kg/day) versus placebo at the 6-month time point (change from baseline -1.7 vs -0.8; p = 0.0024). Bile acid concentration was also significantly reduced with odevixibat versus placebo at month 6 (change from baseline -90 μmol/l vs 22 μmol/l; p = 0.0012). The overall incidence of TEAEs was similar across the odevixibat-treated and placebo groups (74% vs 71%).

In the ASSERT-EXT open-label extension (Ovchinsky et al.) [91], patients in both the odevixibat and placebo arms received odevixibat for an additional 12 weeks. Patients in the placebo-odevixibat arm showed improvements in pruritus after beginning odevixibat, while improvements were sustained in the odevixibat-odevixibat group. The same trends were observed when evaluating reductions in bile acids.