Genetics, pathobiology and therapeutic opportunities of polycystic liver disease

Polycystic liver diseases (PLDs) are inherited genetic disorders characterized by progressive development of intrahepatic, fluid-filled biliary cysts (more than ten), which constitute the main cause of morbidity and markedly affect the quality of life. Liver cysts arise in patients with autosomal dominant PLD (ADPLD) or in co-occurrence with renal cysts in patients with autosomal dominant or autosomal recessive polycystic kidney disease (ADPKD and ARPKD, respectively). Hepatic cystogenesis is a heterogeneous process, with several risk factors increasing the odds of developing larger cysts. Depending on the causative gene, PLDs can arise exclusively in the liver or in parallel with renal cysts. Current therapeutic strategies, mainly based on surgical procedures and/or chronic administration of somatostatin analogues, show modest benefits, with liver transplantation as the only potentially curative option. Increasing research has shed light on the genetic landscape of PLDs and consequent cholangiocyte abnormalities, which can pave the way for discovering new targets for therapy and the design of novel potential treatments for patients. Herein, we provide a critical and comprehensive overview of the latest advances in the field of PLDs, mainly focusing on genetics, pathobiology, risk factors and next-generation therapeutic strategies, highlighting future directions in basic, translational and clinical research. Polycystic liver diseases are genetic disorders that cause hepatic cystogenesis, which can coincide with cyst development in the kidney, with women being more affected than men. This Review discusses the genetics and underlying mechanisms and provides up-to-date therapeutic insights. Key points Mutations in 12 different genes have been linked to the development of polycystic liver disease (PLD) and might explain most of the cases. Most of the affected genes code for proteins that are localized in the endoplasmic reticulum, primary cilium and/or plasma membrane of cholangiocytes. Cystic cholangiocytes are characterized by aberrant proteostasis leading to endoplasmic reticulum stress, autophagy and primary cilium abnormalities, which result in adaptive hyperproliferative, hypersecretory, pro-angiogenic and pro-fibrotic phenotypes. Female gender is considered an important risk factor for the development of symptomatic PLD as oestrogens promote hepatic cystic growth, thus representing a potential target for therapy. The limited long-term benefits provided