Background and Aims Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. Approach A committee of hepatologists, gastroenterologists, pulmonologists, pharmacist, nurse, dietitian, individual with CF, and parent of a child with CF devised “population, intervention, comparison, and outcome” (PICO) questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each PICO question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to formulation of final recommendations. Results 31 PICO questions were assembled, 6,401 manuscripts were title screened for relevance, with 1,053 manuscripts undergoing detailed full text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Conclusions Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment. Export

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree, typically in the setting of inflammatory bowel disease, with an increased risk of liver failure and cholangiocarcinoma. A complex pathophysiology, heterogeneity in clinical features, and the rare nature of the disease have contributed to the lack of effective therapy to date. However, recent innovations in the characterization and prognostication of patients with PSC, in addition to new tools for medical management and emerging pharmacologic agents, give rise to the potential for meaningful progress in the next several years. This review summarizes current concepts in PSC and highlights particular areas in need of further study.

Goals: To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). Background: PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. Study: ATRA (45 mg/m²/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. Results: Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. Conclusions: In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).