Ileal Bile Acid Transporter Blockers for Cholestatic Liver Disease in Pediatric Patients with Alagille Syndrome: A Systematic Review and Meta-Analysis

Abstract

Alagille syndrome (ALGS) is a rare, debilitating inheritable disease that is associated with refractory pruritus due to chronic cholestasis. The following systemic review and meta-analysis presents the latest evidence for ileal bile acid transport (IBAT) blockers in AGLS patients in order to improve their efficacy. This study adhered to PRISMA 2020 Statement guidelines. A systematic search of PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane library was conducted from inception until 23 October 2022. A combination of the following keywords was used: Alagille syndrome, therapeutics, treatment, therapy. Meta-analytical outcomes included effect directions of end-line changes in serum bile acids (sBAs), Itch Scale scores (ItchRO), Multidimensional Fatigue Scale scores, pediatric quality of life (QL), alanine aminotransferase (ALT), and total bilirubin. A total of 94 patients across four trials were enrolled and received maralixibat, odevixibat, or a placebo. There was a significant reduction in ItchRO scores by 1.8 points, as well as in sBAs by 75.8 μmol/L. Both the Multidimensional Fatigue Scale and Pediatric QL scale were also improved by 11.4 and 8.3 points, respectively. However, ALT levels were raised by 40 U/L. The efficacy of IBAT inhibitors across current trials was noted. Future trials may focus on the optimization of dosing regimens, considering gastrointestinal side effects and drug-induced ALT elevation in AGLS patients.

Keywords: Alagille syndrome; chronic cholestasis; maralixibat; odevixibat; refractory pruritus; serum bile acids.

Figure 1

PRISMA study selection process.

Figure 2

Forest plot depicting serum bile acid outcomes [19,20,21,22].

Figure 3

Forest plot depicting Itch Scale outcomes [19,20,21,22].

Figure 4

Forest plot depicting Multidimensional Fatigue Scale outcomes [21,22].

Figure 5

Forest plot depicting PedsQL score outcomes [21,22].

Figure 6

Forest plot representing ALT outcomes at end-line compared to baseline [19,20,21].

Figure 7

Forest plot depicting total bilirubin outcomes at end-line compared to baseline [19,20,21,22].

Figure 8

Risk of bias assessment of RCTs using the ROB 2 and ROBINS-I tools. The traffic light plots depict study-by-study bias assessment [19,20,21,22].

Figure 9

Ileal bile acid transporter (IBAT) blockers in the terminal ileum. Bile acids (BAs) are synthesized in the liver from cholesterol. Common Bas, such as cholic, deoxycholic, chenodeoxycholic, and lithocholic acid, may be combined with glycine or taurine to form conjugated BAs. Once excreted from the liver into the small intestine, most of the conjugated and unconjugated BAs are reabsorbed from the terminal ileum via the ileal bile acid transporter (IBAT) (or apical sodium-dependent bile acid transporter (ASBT, SLC10A2). The BAs reenter the portal circulation with the sodium-dependent taurocholate co-transporting peptide (NCTP, SLC10A2) via the portal vein (not shown). IBAT blockers disrupt the enterohepatic circulation by preventing the uptake of primarily conjugated Bas, whereas unconjugated BAs may be taken back in the liver through organic anion transporters that are less well-defined.