Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis

Abstract

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/day, 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=.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L; P=.001) and C4 (9.8±19 to 7.9±11 ng/mL; P=.03) levels significantly decreased. After washout, ALP and C4 levels non-significantly increased while 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. NCT01456468.

Novel Therapies for Managing Cholestasis

“…All‐ trans retinoic acid (ATRA), which activates the nuclear receptor complex FXR‐Retinoid X receptor (RXR), was evaluated for PSC in a pilot study of UDCA+ATRA and was shown to significantly decrease alanine aminotransferase (ALT) and complement‐4 levels. However, reduction in ALP levels was not significant …”

Vitamin A deficiency in chronic cholestatic liver disease: Is vitamin A therapy beneficial?

“…Among others, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and 7‐α‐hydroxy‐4‐cholesten‐3‐one (C4), a bile acid precursor, were measured at baseline, week 12 and after washout. AtRA treatment in combination with the application of UDCA led to a significant decrease in C4 and in serum ALT . There was also a trend towards a decrease of mean serum ALP, although statistical significance was not reached ( P =.09).…”

“…In 2011, in a collaboration of Yale University and the Mayo Clinic, vitamin A in the form of atRA was orally applied for the first time as an investigational drug in 19 PSC patients with incomplete response to UDCA. 41 All patients enrolled (n=19) received 45 mg atRA per m 2 body surface area and day over a period of 12 weeks followed by a washout period of the same duration. Due to headache (n=2), tinnitus (n=1) and biliary obstruction (n=1) 4 out of 19 patients withdrew.…”

Cenicriviroc, a cytokine receptor antagonist, potentiates all‐trans retinoic acid in reducing liver injury in cholestatic rodents

“…When used alone or in combination with UDCA, atRA significantly reduced the bile acid pool size and improved liver conditions in cholestatic rodent models . A limited clinical trial of atRA in patients with PSC supports this mechanism in humans …”

“…19,20 A limited clinical trial of atRA in patients with PSC supports this mechanism in humans. 21 Cenicriviroc (CVC) is a novel antagonist for both C-C chemokine receptor 2 and 5 (CCR2 & CCR5) that are expressed in many inflammatory cells, including neutrophils, T cells and monocytes. 22,23 It has demonstrated potent anti-inflammatory effects by blocking chemokine-activated immune responses and has been shown to reduce liver fibrosis in animal models of nonalcoholic steatohepatitis (NASH) and alcoholic liver injury.…”