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  • Review Article
  • Published:

Hepatic microcirculation and mechanisms of portal hypertension

Nature Reviews Gastroenterology & Hepatology volume 16, pages 221–234 (2019)Cite this article

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Abstract

The liver microcirculatory milieu, mainly composed of liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs) and hepatic macrophages, has an essential role in liver homeostasis, including in preserving hepatocyte function, regulating the vascular tone and controlling inflammation. Liver microcirculatory dysfunction is one of the key mechanisms that promotes the progression of chronic liver disease (also termed cirrhosis) and the development of its major clinical complication, portal hypertension. In the present Review, we describe the current knowledge of liver microcirculatory dysfunction in cirrhotic portal hypertension and appraise the preclinical models used to study the liver circulation. We also provide a comprehensive summary of the promising therapeutic options to target the liver microvasculature in cirrhosis.

Key points

  • Portal hypertension is the most important non-neoplastic complication of chronic liver disease, leading to high morbidity and mortality.

  • A pathological increase in intrahepatic vascular resistance, which derives from profound deregulation in the phenotype of all hepatic cell types, is the primary factor in the development of portal hypertension.

  • Mechanisms leading to increased intrahepatic vascular resistance in cirrhosis are thought to include overactivation of vasoconstrictor pathways and downregulation of vasodilator signalling in the sinusoidal milieu.

  • Treatments targeting intrahepatic vascular resistance developed in preclinical models have exhibited very low success at the bedside, encouraging further research and the development of new models.

  • Current methods to understand the pathophysiology of portal hypertension and develop new therapeutics include preclinical animals models, conventional in vitro approaches and new in vitro methods that combine biological scaffolds with primary cells.

  • Improved characterization of portal hypertension pathophysiology and discovery of new therapeutic targets need to be done using preclinical models that mimic the clinical scenario and consider the current epidemiology of the disease.

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Fig. 1: The intrahepatic component of portal hypertension pathophysiology.
Fig. 2: The liver sinusoid.
Fig. 3: Advanced in vitro models mimicking the liver.

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Acknowledgements

J.G.-S. has received funding from the Instituto de Salud Carlos III (currently, FIS PI17/00012), the Spanish Ministry of Science, Innovation and Universities, the Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBEREHD), the European Union Funds FEDER “una manera de hacer Europa” and the Stiftung für Leberkrankheiten. A.F.-I. has a postdoctoral fellowship from the Instituto de Salud Carlos III (Sara Borrell programme CD15/00050).

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Nature Reviews Gastroenterology & Hepatology thanks S. Moeller and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain

    Jordi Gracia-Sancho, Giusi Marrone & Anabel Fernández-Iglesias

  2. Hepatology, Department of Biomedical Research, Inselspital, Bern University, Bern, Switzerland

    Jordi Gracia-Sancho

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Gracia-Sancho, J., Marrone, G. & Fernández-Iglesias, A. Hepatic microcirculation and mechanisms of portal hypertension. Nat Rev Gastroenterol Hepatol 16, 221–234 (2019). https://doi.org/10.1038/s41575-018-0097-3

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