Serum Bile Acid Profiling and Mixed Model Analysis Reveal Biomarkers Associated with Pruritus Reduction in Maralixibat-Treated Patients with BSEP Deficiency

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is a debilitating disease manifest by severe cholestasis, intractable pruritus and growth delay that ultimately leads to liver failure or transplantation. Maralixibat (MRX) was recently approved for the treatment of cholestatic pruritus in patients with Alagille syndrome. The aim of this study was to determine whether specific changes in the composition of the serum bile acid metabolome could predict pruritus response to treatment. Serum BAs (sBA) and 7α-hydroxy-4-cholesten-3-one (7α-C4), a surrogate marker of BA synthesis, were monitored by ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry over 72 weeks in PFIC patients with mild to moderate non-truncating bile salt export pump (BSEP) mutations (n = 19) treated with MRX. The weekly itch reported outcome observer (ItchRO[Obs]) score measured pruritus severity. Linear mixed models (LMM) were applied to explore the effects of individual sBA profiles and their relationship to pruritus response. Changes in the composition of sBA correlated with pruritus improvement. Notably, the trajectory of serum total and individual BA species and 7α-C4 were significantly associated with ItchRO[Obs] score (p < 0.05). These results reveal that beyond simple total sBA concentrations, specific changes to the BA metabolome are associated with pruritus reduction in patients with BSEP deficiency, thus providing further insight into causal relationship of bile acids and pruritus.

Opinion paper on the diagnosis and treatment of progressive familial intrahepatic cholestasis

“…In addition, liver synthesis and development of fibrosis/cirrhosis with associated complications should be monitored. The literature review highlighted a number of diagnostic tools that may enable effective monitoring of a patient’s quality of life and levels of pruritus, including PRUCISION and ItchRO(Observer) 53 , 58 which have been validated and could be used within clinical practice. New biomarkers are emerging (such as the potential to monitor disease progression by assessing markers of fibrosis 54 ); however, further research into their clinical utility is required.…”

“…Progression of PFIC can vary widely between individuals, 2 and several biomarkers have been reported as surrogate indicators of disease progression. 28 , 30 , 31 , 32 , 36 , 37 , 38 , 53 , 54 Notably, a decrease in SBA levels has been shown to correlate with reduction in pruritus severity. 55 In addition, elevated circulating values have also been linked with poor native liver survival in children.…”

“…Sleep disturbance, growth retardation, total and conjugated bilirubin levels, and poor quality of life have all been associated with PFIC, and lend themselves to use as markers of disease progression. 29 , 30 , 36 , 38 , 53 , 56 , 57 Other biomarkers cited in the literature include markers of fibrosis, including APRI (aspartate aminotransferase-to-platelet ratio index) and FIB-4 (fibrosis-4 index). 53 Validated tools to monitor some of these markers have been developed, such as ItchRO(Observer) and PRUCISION for pruritus and sleep disturbance.…”

“… 29 , 30 , 36 , 38 , 53 , 56 , 57 Other biomarkers cited in the literature include markers of fibrosis, including APRI (aspartate aminotransferase-to-platelet ratio index) and FIB-4 (fibrosis-4 index). 53 Validated tools to monitor some of these markers have been developed, such as ItchRO(Observer) and PRUCISION for pruritus and sleep disturbance. 53 , 58 In addition, a liver histology scoring system for BSEP deficiency has also been described for monitoring microscopic changes in clinical practice and as a surrogate endpoint in clinical trials.…”

“… 53 Validated tools to monitor some of these markers have been developed, such as ItchRO(Observer) and PRUCISION for pruritus and sleep disturbance. 53 , 58 In addition, a liver histology scoring system for BSEP deficiency has also been described for monitoring microscopic changes in clinical practice and as a surrogate endpoint in clinical trials. 54 …”