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Aliment Pharmacol Ther 2012; 35: 255-265 Summary Background Primary sclerosing cholangitis (PSC) is characterised by progressive inflammatory and fibrotic destruction of the biliary ducts. There are no effective medical therapies and presently high dose ursodeoxycholic acid is no longer recommended due to significant adverse events in a recent clinical trial. Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is associated with PSC in both children and adults. Since CFTR dysfunction leads to altered fatty acid metabolism, specifically reduced docosahexaenoic acid (DHA), we hypothesised that DHA supplementation might be an effective therapy for patients with PSC. Aim To determine the safety and efficacy of oral DHA supplementation for the treatment of PSC. Methods We conducted a 12 month open-label pilot study to evaluate safety of oral DHA and its effects on serum alkaline phosphatase as a primary outcome measure in 23 patients with PSC. DHA was administered orally at 800 mg twice per day. Secondary outcomes included changes in other liver function tests and fibrosis biomarkers. Results A 1.7-fold increase in serum DHA levels was observed with supplementation. The mean alkaline phosphatase level (±S.E.) at baseline was 357.8 ± 37.1 IU compared to 297.1 ± 23.7 IU ( P < 0.05) after 12 months of treatment. There were no changes in other liver function tests and fibrosis biomarkers. No adverse events were reported. Conclusions Oral DHA supplementation is associated with an increase in serum DHA levels and a significant decline in alkaline phosphatase levels in patients with PSC. These data support the need for a rigorous trial of DHA therapy in PSC. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2011; 34: 1185-1192 Summary Background Ursodeoxycholic acid (UDCA) in a dose of 28-30 mg/kg/day increases the likelihood of clinical deterioration of primary sclerosing cholangitis (PSC) patients. Aim To compare the risk of adverse clinical endpoints in patients with varying disease status. Methods We reviewed records from patients previously enrolled in a study evaluating the effects of high dose (28-30 mg/kg/day) UDCA in PSC. Patients were grouped according to treatment (UDCA vs. placebo) and baseline disease status (histological stage of PSC, total serum bilirubin). Development of clinical endpoints including death, liver transplantation, cirrhosis, oesophageal varices and cholangiocarcinoma was sought. Results A total of 150 patients were included of whom 49 patients developed endpoints. There was an increased development of endpoints among patients using UDCA vs. placebo (14 vs. 4, P = 0.0151) with early histological disease (stage 1-2, n = 88) but not with late stage (stage 3-4, n = 62) disease (17 vs. 14, P = 0.2031). Occurrence of clinical endpoints was also higher in patients receiving UDCA vs. placebo (16 vs. 2, P = 0.0008) with normal bilirubin levels (total bilirubin ≤1.0 mg/dL) but not in patients with elevated bilirubin levels (15 vs. 16, P = 0.6018). Among patients not reaching endpoints 31.7% had normalisation of their alkaline phosphatase levels when compared to 14.3% in patients who reached endpoints ( P = 0.073). Conclusion The increased risk of adverse events with UDCA treatment when compared with placebo is only apparent in patients with early histological stage disease or normal total bilirubin. [ABSTRACT FROM AUTHOR]

Background Newer therapies are needed for patients with primary biliary cirrhosis and incomplete response to ursodeoxycholic acid (UDCA). Fenofibrate is a fibric acid postulated to regulate immune response and cell proliferation. Aim To evaluate the efficacy and safety of fenofibrate in patients with primary biliary cirrhosis and incomplete response to UDCA. Methods We undertook a pilot study involving 20 patients with primary biliary cirrhosis and serum alkaline phosphatase (ALP) ⩾ 2× ULN. Nonparametric statistical tests and Spearman correlation test were used as appropriate. Results Twenty patients received fenofibrate (160 mg/ day) in addition to UDCA for 48 weeks. Median serum ALP decreased significantly at 48 weeks compared with baseline values [351 (214-779) U/L at baseline vs. 177 (60- 384) U/ L at 48 weeks, P < 0.05]. A rebound in ALP occurred upon drug discontinuation. Serum aspartate aminotransferase and Immunoglobulin M also decreased significantly, while bilirubin and albumin remained unchanged. Median IL-1 decreased from 28.9 (2.7-10 000) to 11.3 (2.5- 277.7) pg /mL (P = 0.049), and median IL-6 from 4.6 (3.2-5205) to 3.5 (3.2-73.4) pg /mL (P = 0.027). Heartburn was the most frequent adverse event, leading to discontinuation of two study subjects. Conclusions Combination therapy of fenofibrate and UDCA induced significant biochemical improvement in patients with primary biliary cirrhosis and incomplete response to UDCA. Further studies are warranted. [ABSTRACT FROM AUTHOR]