Polycystic Liver Disease: Advances in Understanding and Treatment

Overview

Journal Annu Rev Pathol

Publisher Annual Reviews

Specialty Pathology

Date 2021 Nov 1

PMID 34724412

Citations 7

Authors

Tatyana V Masyuk

Anatoliy I Masyuk

Nicholas F LaRusso

Affiliations

Soon will be listed here.

Abstract

Polycystic liver disease (PLD) is a group of genetic disorders characterized by progressive development of cholangiocyte-derived fluid-filled hepatic cysts. PLD is the most common manifestation of autosomal dominant and autosomal recessive polycystic kidney diseases and rarely occurs as autosomal dominant PLD. The mechanisms of PLD are a sequence of the primary (mutations in PLD-causative genes), secondary (initiation of cyst formation), and tertiary (progression of hepatic cystogenesis) interconnected molecular and cellular events in cholangiocytes. Nonsurgical, surgical, and limited pharmacological treatment options are currently available for clinical management of PLD. Substantial evidence suggests that pharmacological targeting of the signaling pathways and intracellular processes involved in the progression of hepatic cystogenesis is beneficial for PLD. Many of these targets have been evaluated in preclinical and clinical trials. In this review, we discuss the genetic, molecular, and cellular mechanisms of PLD and clinical and preclinical treatment strategies.

Citing Articles

Hepatobiliary organoid research: the progress and applications.

Zou R, Dai Y, Liu F, Yang S, Hu H, Li F Front Pharmacol. 2025; 16:1473863.

PMID: 40008122 PMC: 11850396. DOI: 10.3389/fphar.2025.1473863.

NAMPT Overexpression Drives Cell Growth in Polycystic Liver Disease through Mitochondrial Metabolism Regulation.

Pant K, Gradilone S Am J Pathol. 2024; 194(8):1528-1537.

PMID: 38849029 PMC: 11284764. DOI: 10.1016/j.ajpath.2024.04.010.

Polycystic liver disease: An uncommon genetic condition.

Limaiem F, Hajri M Clin Case Rep. 2024; 12(5):e8892.

PMID: 38711839 PMC: 11070482. DOI: 10.1002/ccr3.8892.

Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease.

Zhang C, Rehman M, Tian X, Pei S, Gu J, Bell 3rd T Nat Commun. 2024; 15(1):3698.

PMID: 38693102 PMC: 11063051. DOI: 10.1038/s41467-024-48025-6.

Comparative analysis of SEC61A1 mutant R236C in two patient-derived cellular platforms.

Weiand M, Sandfort V, Nadzemova O, Schierwagen R, Trebicka J, Schlevogt B Sci Rep. 2024; 14(1):9506.

PMID: 38664472 PMC: 11045796. DOI: 10.1038/s41598-024-59033-3.

References

Boerrigter M, Bongers E, Lugtenberg D, Nevens F, Drenth J . Polycystic liver disease genes: Practical considerations for genetic testing. Eur J Med Genet. 2021; 64(3):104160. DOI: 10.1016/j.ejmg.2021.104160. View

Neijenhuis M, Kievit W, Verheesen S, DAgnolo H, Gevers T, Drenth J . Impact of liver volume on polycystic liver disease-related symptoms and quality of life. United European Gastroenterol J. 2018; 6(1):81-88. PMC: 5802666. DOI: 10.1177/2050640617705577. View

Griffiths J, Mills M, Ong A . Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis. BMJ Open. 2020; 10(1):e032620. PMC: 6955551. DOI: 10.1136/bmjopen-2019-032620. View

Lee-Law P, Olaizola P, Caballero-Camino F, Izquierdo-Sanchez L, Rodrigues P, Santos-Laso A . Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models. J Hepatol. 2020; 74(2):394-406. PMC: 8157180. DOI: 10.1016/j.jhep.2020.09.010. View

Lorenzo Pisarello M, Masyuk T, Gradilone S, Masyuk A, Ding J, Lee P . Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease. Am J Pathol. 2018; 188(4):981-994. PMC: 5963486. DOI: 10.1016/j.ajpath.2017.12.016. View

Norio R . Polycystic disease of liver: an entity of its own or not?. Clin Genet. 1983; 23(1):78-9. DOI: 10.1111/j.1399-0004.1983.tb00441.x. View

Masyuk A, Masyuk T, Lorenzo Pisarello M, Ding J, Loarca L, Huang B . Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target. Hepatology. 2017; 67(3):1088-1108. PMC: 5826832. DOI: 10.1002/hep.29577. View

Masyuk T, Masyuk A, LaRusso N . MicroRNAs in cholangiociliopathies. Cell Cycle. 2009; 8(9):1324-8. PMC: 3839534. DOI: 10.4161/cc.8.9.8253. View

Hoevenaren I, Wester R, Schrier R, McFann K, Brian Doctor R, Drenth J . Polycystic liver: clinical characteristics of patients with isolated polycystic liver disease compared with patients with polycystic liver and autosomal dominant polycystic kidney disease. Liver Int. 2007; 28(2):264-70. DOI: 10.1111/j.1478-3231.2007.01595.x. View

10.

Amura C, Brodsky K, Groff R, Gattone V, Voelkel N, Brian Doctor R . VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice. Am J Physiol Cell Physiol. 2007; 293(1):C419-28. DOI: 10.1152/ajpcell.00038.2007. View

11.

Barten T, Bernts L, Drenth J, Gevers T . New insights into targeting hepatic cystogenesis in autosomal dominant polycystic liver and kidney disease. Expert Opin Ther Targets. 2020; 24(6):589-599. DOI: 10.1080/14728222.2020.1751818. View

12.

Cnossen W, Te Morsche R, Hoischen A, Gilissen C, Venselaar H, Mehdi S . LRP5 variants may contribute to ADPKD. Eur J Hum Genet. 2015; 24(2):237-42. PMC: 4717208. DOI: 10.1038/ejhg.2015.86. View

13.

Cnossen W, Te Morsche R, Hoischen A, Gilissen C, Chrispijn M, Venselaar H . Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis. Proc Natl Acad Sci U S A. 2014; 111(14):5343-8. PMC: 3986119. DOI: 10.1073/pnas.1309438111. View

14.

Strazzabosco M, Fiorotto R, Melero S, Glaser S, Francis H, Spirli C . Differentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulation. Hepatology. 2009; 50(1):244-52. PMC: 2738985. DOI: 10.1002/hep.22926. View

15.

Besse W, Chang A, Luo J, Triffo W, Moore B, Gulati A . Mutation Carriers Develop Kidney and Liver Cysts. J Am Soc Nephrol. 2019; 30(11):2091-2102. PMC: 6830805. DOI: 10.1681/ASN.2019030298. View

16.

Masyuk T, Masyuk A, LaRusso N . Cholangiociliopathies: genetics, molecular mechanisms and potential therapies. Curr Opin Gastroenterol. 2009; 25(3):265-71. PMC: 3831343. DOI: 10.1097/MOG.0b013e328328f4ff. View

17.

Qian Q, Du H, King B, Kumar S, Dean P, Cosio F . Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol. 2008; 19(3):631-8. PMC: 2391057. DOI: 10.1681/ASN.2007050626. View

18.

Lu H, Galeano M, Ott E, Kaeslin G, Kausalya P, Kramer C . Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nat Genet. 2017; 49(7):1025-1034. PMC: 5687889. DOI: 10.1038/ng.3871. View

19.

Renken C, Fischer D, Kundt G, Gretz N, Haffner D . Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats. Nephrol Dial Transplant. 2010; 26(1):92-100. DOI: 10.1093/ndt/gfq384. View

20.

Gevers T, Drenth J . Diagnosis and management of polycystic liver disease. Nat Rev Gastroenterol Hepatol. 2013; 10(2):101-8. DOI: 10.1038/nrgastro.2012.254. View