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Genetics, pathobiology and therapeutic opportunities of polycystic liver disease

Nature Reviews Gastroenterology & Hepatology volume 19, pages 585–604 (2022)Cite this article

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Abstract

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.

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 by the current clinical therapeutic approaches based on somatostatin analogues point out the necessity of developing novel therapeutic strategies to halt hepatic cystogenesis.

  • Future clinical trials should consider combinatory therapeutic regimens that target key dysregulated processes in PLD.

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Fig. 1: Mutated genes in polycystic liver disease.
Fig. 2: Proposed mechanisms related to hepatic cystogenesis.
Fig. 3: Signalling pathways responsible for hepatic cystogenesis development and progression.

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Acknowledgements

The authors thank the following for their grant support: Spanish Carlos III Health Institute (ISCIII) (J.M.B. (FIS PI18/01075, PI21/00922 and Miguel Servet Programme CPII19/00008), M.J.P. (FIS PI14/00399, FIS PI17/00022 and Ramon y Cajal Programme RYC-2015-17755), P.M.R. (Sara Borrell (CD19/00254))), cofinanced by ‘Fondo Europeo de Desarrollo Regional’ (FEDER); CIBERehd (ISCIII): J.M.B., L.B., P.A., P.M.R. and M.J.P.; ‘Diputación Foral de Gipuzkoa’ (2020-CIEN-000067-01 to P.M.R.), Department of Health of the Basque Country (2019111024 to M.J.P., 2017111010 to J.M.B. and 2020111077 to J.M.B. and P.A.), ‘Euskadi RIS3’ (2016222001, 2017222014, 2018222029, 2019222054, 2020333010 to J.M.B.), Department of Industry of the Basque Country (Elkartek KK-2020/00008 to J.M.B.); ‘Fundación Científica de la Asociación Española Contra el Cáncer’ (AECC Scientific Foundation to J.M.B.); La Caixa Scientific Foundation (HR17-00601 to J.M.B.); AMMF–The Cholangiocarcinoma Charity (EU/2019/AMMFt/001 to J.M.B. and P.M.R.); PSC Partners US (to J.M.B.) and PSC Supports UK (06119JB to J.M.B.); European Union Horizon 2020 Research and Innovation Program (825510, ESCALON, to J.M.B.); ‘Ayudas para apoyar grupos de investigación del sistema Universitario Vasco’ (IT971-16 to P.A.), MCIU/AEI/FEDER, UE (2018-095134-B-100 to P.A.) and by the University of Basque Country (COLAB20/01 to P.A. and MARSA21/17 to F.J.C.-C. funded by the Spanish Ministry of Universities and European Union-Next Generation EU).

Author information

Author notes

  1. These authors contributed equally: Paula Olaizola, Pedro M. Rodrigues.

  2. These authors jointly supervised this work: Maria J. Perugorria, Jesus M. Banales.

Authors and Affiliations

  1. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute–Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain

    Paula Olaizola, Pedro M. Rodrigues, Francisco J. Caballero-Camino, Laura Izquierdo-Sanchez, Luis Bujanda, Maria J. Perugorria & Jesus M. Banales

  2. National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), San Sebastian-Donostia, Spain

    Pedro M. Rodrigues, Patricia Aspichueta, Luis Bujanda, Maria J. Perugorria & Jesus M. Banales

  3. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

    Pedro M. Rodrigues & Jesus M. Banales

  4. Departments of Medicine and Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain

    Patricia Aspichueta, Luis Bujanda & Maria J. Perugorria

  5. Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain

    Patricia Aspichueta

  6. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    Nicholas F. Larusso

  7. Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands

    Joost P. H. Drenth

  8. Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain

    Jesus M. Banales

Authors
  1. Paula Olaizola
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  2. Pedro M. Rodrigues
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  3. Francisco J. Caballero-Camino
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  4. Laura Izquierdo-Sanchez
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  5. Patricia Aspichueta
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  6. Luis Bujanda
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  7. Nicholas F. Larusso
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  8. Joost P. H. Drenth
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  9. Maria J. Perugorria
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  10. Jesus M. Banales
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Contributions

P.O., P.M.R., F.J.C.-C. and L.I.-S. researched data for the article. J.M.B., P.O., P.M.R., F.J.C.-C., L.I.-S., M.J.P. and J.P.H.D. contributed substantially to discussion of the content. P.O., P.M.R., F.J.C.C. and L.I.-S. wrote the article. J.M.B., P.O., P.M.R., P.A., L.B., N.F.L., M.J.P. and J.P.H.D. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Jesus M. Banales.

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Competing interests

J.M.B. received grants and consultancy from Albireo. J.P.H.D. and J.M.B. are members of the European Reference Network for Rare Liver Diseases. All other authors declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks Carsten Bergmann, Luca Fabris and Marco Marzioni for their contribution to the peer review of this work.

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Olaizola, P., Rodrigues, P.M., Caballero-Camino, F.J. et al. Genetics, pathobiology and therapeutic opportunities of polycystic liver disease. Nat Rev Gastroenterol Hepatol 19, 585–604 (2022). https://doi.org/10.1038/s41575-022-00617-7

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