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BackgroundPrimary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC.MethodsThis open-label study evaluated the safety and tolerability of maralixibat ≤10mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed.ResultsOf 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline.ConclusionsMaralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.

Over the last decade, the use of liver grafts from hepatitis C virus antibody-positive donors [HCV(+)Ds] has tripled in the United States. Although previous studies have demonstrated no association between an HCV(+)D status and graft loss, the effects of an HCV(+)D on histological outcomes are not well known. Hepatitis C virus (HCV)-infected recipients at 5 US centers (2002-2007) who survived more than 30 days with 1 or more posttransplant biopsy samples were included. Cox regression was used to examine the association between an HCV(+)D status and advanced fibrosis (stage 3/4 or higher). Ninety-nine of the 1206 patients (8%) received an HCV(+)D graft. Recipients of HCV(+)D grafts were older than recipients of hepatitis C virus antibody-negative donor [HCV(-)D] grafts (P = 0.03), but they were otherwise similar. HCV(+)D grafts were significantly lower in quality according to the donor risk index (P0.001). Advanced fibrosis occurred in 32% of HCV(+)D graft recipients and in 28% of HCV(-)D graft recipients (P = 0.39). The unadjusted 1- and 3-year rates of advanced fibrosis were significantly higher for HCV(+)D graft recipients (14% and 48%) versus HCV(-)D graft recipients (7% and 33%, P = 0.01). Transplantation with HCV(+)D grafts was associated with a 58% increased risk of advanced fibrosis [95% confidence interval (CI) = 1.05-2.36, P = 0.03]. However, in an analysis stratified by the mean donor age of 45 years, an HCV(+)D status was associated with advanced fibrosis only with donors45 years old [hazard ratio (HR) = 1.76, 95% CI = 1.06-2.93, P = 0.03] and not with donors ≤45 years old (HR = 0.94, 95% CI = 0.47-1.87, P = 0.85). In conclusion, a careful consideration of the risks and benefits is needed with HCV(+)D grafts. Recipients of HCV(+)D grafts (especially from older donors) should undergo close monitoring for more rapidly progressive fibrosis. Studies are needed to determine whether early HCV therapy modifies this risk.

As long-term survival after liver transplantation increases, metabolic complications are becoming increasingly prevalent. Given concerns about which group of providers should be managing liver recipients and how well metabolic complications are managed, we administered a postal survey to 280 transplant hepatologists to determine attitudes, perceptions, and practice patterns in the management of metabolic complications after transplantation. The response rate was 68.2%. There was great variation in patterns of practice across the United States with respect to the number of posttransplant clinics, clinic format, and number of recipients cared for per week. Hepatologists, primary care physicians (PCPs), and surgeons were primarily responsible for the overall care of liver recipients 1 year or more after liver transplantation according to 66%, 24%, and 8% of respondents, respectively. Hepatologists felt that metabolic complications were common, but few strongly agreed that hypertension (33.3%), chronic renal insufficiency (3.8%), diabetes mellitus (8.8%), dyslipidemia (11.1%), and bone disease (12.8%) were well controlled. The majority of hepatologists indicated that ideally PCPs should be managing recipients' hypertension, diabetes mellitus, dyslipidemia, and bone disease (78.8%, 63.1%, 78.3%, and 72.5%), but they felt that in actuality, PCPs were managing these conditions less frequently (45.4%, 51.4%, 44.6%, and 38%). In conclusion, metabolic complications are perceived to be common but not well controlled post-transplant, and most hepatologists feel that PCPs should take a more active role in the management of these complications. Future studies are needed to identify barriers to care in the treatment of metabolic complications post-transplant with the goal of improving long-term morbidity and mortality.