Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy

Abstract

Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.

Keywords: ACE2, angiogenesis-converting enzyme 2; ACLF, acute-on-chronic liver failure; AT1R, angiotensin II type I receptor; CCL2, chemokine (C-C motif) ligand 2; CCl4, carbon tetrachloride; CLD, chronic liver disease; CSPH, clinically significant portal hypertension; Dll4, delta like canonical Notch ligand 4; ECM, extracellular matrix; EUS, endoscopic ultrasound; FXR; FXR, farnesoid X receptor; HCC, hepatocellular carcinoma; HRS, hepatorenal syndrome; HSC; HSCs, hepatic stellate cells; HVPG, hepatic venous pressure gradient; Hsp90, heat shock protein 90; JAK2, Janus kinase 2; KO, knockout; LSEC; LSEC, liver sinusoidal endothelial cells; MLCP, myosin light-chain phosphatase; NET, neutrophil extracellular trap; NO; NO, nitric oxide; NSBB; NSBBs, non-selective beta blockers; PDE, phosphodiesterase; PDGF, platelet-derived growth factor; PIGF, placental growth factor; PKG, cGMP-dependent protein kinase; Rho-kinase; TIPS; TIPS, transjugular intrahepatic portosystemic shunt; VCAM1, vascular cell adhesion molecule 1; VEGF; VEGF, vascular endothelial growth factor; angiogenesis; eNOS, endothelial nitric oxide synthase; fibrosis; liver stiffness; statins; β-Arr2, β-arrestin 2; β1-AR, β1-adrenergic receptor; β2-AR, β2-adrenergic receptor.

Fig. 1

Liver sinusoidal cell dysfunction in liver pathogenesis. Normal LSEC function is necessary for liver homeostasis. Various aetiologies can cause LSECs to become dysfunctional, leading to disease progression. Capillarisation is the loss of fenestrae and appearance of a basement membrane in LSECs. eNOS-derived NO plays a pivotal role in liver homeostasis by regulating vascular tone, maintaining fenestrae, maintaining HSCs in a quiescent state and blocking platelet attachments to endothelial cells among other functions. LSEC dysfunction often precedes pathological events, including inflammation, NET formation, microvascular thrombosis, parenchymal extinction (regions of tissue loss and fibrosis secondary to vascular obstruction and microvascular thrombosis), hepatocyte injury and fibrosis, leading to the development of portal hypertension. By contrast, in HSCs, calcium-independent contraction is mainly regulated by MLCP, which is inhibited by the RhoA/Rho-kinase pathway and activated by the NO/PKG-pathway. CXCL1, chemokine (C-X-C motif) ligand 1; HSCs, hepatic stellate cells; ICAM, intercellular adhesion molecule; LSECs, liver sinusoidal endothelial cells; MLCP, myosin light-chain phosphatase; NO, nitric oxide; NET, neutrophil extracellular trap; PKG, cGMP-dependent kinase; VCAM, vascular cell adhesion molecule.

Fig. 2

Biological processes and molecular functions in primary human HSCs. Treemap representation of biological processes (A) and molecular functions (B) revealed by RNA-sequencing (transcriptome analysis) of human primary HSCs. The Treemap plot shows a two-level hierarchy of GO terms. Each rectangle is a GO term cluster representative. The representatives are joined together to loosely related GO terms and visualised. The size of the rectangles reflects the significance (p value) of the respective GO term. GoRilla was used in combination with REVIGO and R-studio (V1.3.1093) with packages TmPlot and TreeMap (R-Studio Team (2020). http://www.rstudio.com/) for the visualisation and GO term determination. The details of the pathways involved in the biological processes are found in Table S1 and the molecular functions in Table S2. GO, gene ontology; HSCs, hepatic stellate cells.

Fig. 3

Word cloud representing the most frequent keywords of abstracts with the keyword gut-liver axis. The size of the words within the word cloud correlates with the frequency of the respective word in the analysed abstract text.