Cholestatic Itch: Our Current Understanding of Pathophysiology and Treatments

Hepatic pruritus is common in liver conditions, including cholestasis and nonalcoholic fatty liver disease. The pruritus can be severe enough to diminish sleep and decrease quality of life. The pathophysiology likely involves many molecules and receptors, including bile acids, bilirubin, lysophosphatidic acid (LPA), endogenous opioids, and serotonin. Recent advances suggest a significant role of Mas-related G protein-coupled receptor X4 (MRGPRX4) and autotaxin/LPA as key players in cholestatic pruritus. Further research is needed to develop increasingly targeted therapies with greater efficacy, especially given that many patients report itch refractory to various treatments. Cholestyramine was the only US FDA-approved drug for cholestatic pruritus until recent approval of ileal bile acid transporter (IBAT) inhibitors for use in the pediatric cholestatic conditions, progressive familial intrahepatic cholestasis and Alagille syndrome. Both medications decrease the bile acid pool. IBAT inhibitors are under investigation for broader use, and targeting LPA receptors and MRGPR4 are additional attractive options.