Alagille syndrome (ALGS) and
progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie
cholestasis),
pruritus and potentially fatal
liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically,
bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of
bile acids leads to their accumulation in the liver, which is thought to underlie
pruritus and liver-damaging
inflammation. One approach to reducing pathologic
bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting
bile acids to an external stoma). These procedures can normalize serum
bile acids, reduce
pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal
bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs
bile acids from the intestine. IBAT inhibition has been shown to reduce serum
bile acids and
pruritus in trials of paediatric cholestatic
liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic
liver diseases including ALGS and PFIC.