Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Abstract

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.

Keywords: bile acids and salts; cholestasis; paediatrics; pruritus; sodium-bile acid cotransporter.

Figure 1

Role of IBAT, bile acids and enterohepatic circulation in homeostasis and disease. A, Bile acids, synthesized in and secreted from the liver, travel to the small intestine where they aid in digestion and absorption of nutrients. Bile acids are reabsorbed from the terminal ileum by IBAT (95%) and return to the liver through the portal veins (indicated by the red line). This cycle is known as enterohepatic circulation. Bile acids not recovered in this process are replaced by nascent synthesis (5%), which is governed by inhibitory feedback from FGF19. The synthesis intermediate C4 is frequently used as a readout of bile acid synthesis. High bile acid levels in the ileum prompt FGF19 signalling, which suppresses further bile acid production (indicated by a decrease in C4 levels). Typical bile acid concentrations in liver cells, the biliary and intestinal tracts and the portal circulation are given in milli‐ or micromolar quantities, as applicable. ¹ B, Pharmacologic inhibition of IBAT (the ileal bile acid transporter), a novel strategy being explored as treatment for Alagille syndrome and progressive familial intrahepatic cholestasis, prevents the recirculation of bile acids, shunting them away from the liver and towards faecal excretion instead, which is expected to reduce the overall size of the bile acid pool. C4 (7α‐hydroxy‐4‐cholesten‐3‐one), bile acid precursor; FGF19, fibroblast growth factor 19 ³