Polycystic Liver Disease: Advances in Understanding and Treatment

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.

Keywords: cholangiocytes; cystogenesis; genetics; mechanisms; polycystic liver disease; therapy.

Figure 1

Hepatic cystogenesis in (a) patients and (b-d) animal models with different forms of PLD. Disease-causative genes are shown in parentheses. Despite genetic heterogeneity, mutations in PLD-causative genes result in similar end points—multiple hepatic cysts of different sizes and shapes. (a,b) Immunofluorescence confocal microscopy. (c) Scanning electron microscopy. (d) Gross appearance. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ADPLD, autosomal dominant polycystic liver disease; ARPKD, autosomal recessive polycystic kidney disease; PLD, polycystic liver disease; TGR5, Takeda G protein-coupled receptor 5. Panel c adapted from Reference with permission from Elsevier.

Figure 2

The mechanisms of hepatic cystogenesis: a sequence of the interconnected molecular and cellular (a) primary, (b) secondary, and (c) tertiary events in cholangiocytes. In panel a, PLD-associated genes are shown in blue and respective protein products are shown in black. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ADPLD, autosomal dominant polycystic liver disease; ARPKD, autosomal recessive polycystic kidney disease; PLD, polycystic liver disease; PLDC, polycystic liver disease cholangiocyte.

Figure 3

Pathways dysregulated in PLD. Transcriptome profiling of NHCs and PLDCs revealed that out of 11,897 transcripts present in both cell lines, 6,500 transcripts were differentially expressed in PLDCs (i.e., up- or downregulated). Functional annotation clustering of these transcripts by the Kyoto Encyclopedia of Genes and Genomes pathways indicates 30 altered pathways in PLDCs. Abbreviations: cAMP, cyclic adenosine monophosphate; CDC25, cell division cycle 25; CREB, cAMP-response element-binding protein; ECM, extracellular matrix; EGF, endothelial growth factor; ERK, extracellular signal-regulated kinase; MAP, mitogen-activated protein; mTOR mammalian target of rapamycin; NHC, normal human cholangiocyte; PI3, phosphoinositide 3; PLD, polycystic liver disease; PLDC, polycystic liver disease cholangiocyte; TGF, transforming growth factor; VEGF, vascular endothelial growth factor. Scanning electron microscope image adapted with permission from Reference .

Figure 4

Classification criteria for polycystic liver disease severity, clinical presentation, symptoms, and treatment options. Gigot and Schnelldorfer classifications are based on the number and size of the cysts and the remaining liver parenchyma. Abdominal magnetic resonance imaging images provided by Dr. M. Hogan.

Figure 5

Therapeutic interventions in PLD. Abbreviations: AC5, adenylyl cyclase 5; AMPK, AMP-activated protein kinase; Cdc25A, cell division cycle 25A; ER, endoplasmic reticulum; HDAC, histone deacetylase; HSP, heat shock protein; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; PLD, polycystic liver disease; PPAR peroxisome proliferator-activated receptor; RAF, rapidly accelerated fibrosarcoma; SST, somatostatin; SUMO, small ubiquitin-like modifier; TGR5, Takeda G protein–coupled receptor 5; TRPV, transient receptor potential vanilloid; UDCA, ursodeoxycholic acid; VEGFR, vascular endothelial growth factor receptor.