Regression of portal hypertension: underlying mechanisms and therapeutic strategies

Sonia Selicean, Cong Wang, Sergi Guixé-Muntet, Horia Stefanescu, Norifumi Kawada, Jordi Gracia-Sancho, Sonia Selicean, Cong Wang, Sergi Guixé-Muntet, Horia Stefanescu, Norifumi Kawada, Jordi Gracia-Sancho

Abstract

Portal hypertension is the main non-neoplastic complication of chronic liver disease, being the cause of important life-threatening events including the development of ascites or variceal bleeding. The primary factor in the development of portal hypertension is a pathological increase in the intrahepatic vascular resistance, due to liver microcirculatory dysfunction, which is subsequently aggravated by extra-hepatic vascular disturbances including elevation of portal blood inflow. Evidence from pre-clinical models of cirrhosis has demonstrated that portal hypertension and chronic liver disease can be reversible if the injurious etiological agent is removed and can be further promoted using pharmacological therapy. These important observations have been partially demonstrated in clinical studies. This paper aims at providing an updated review of the currently available data regarding spontaneous and drug-promoted regression of portal hypertension, paying special attention to the clinical evidence. It also considers pathophysiological caveats that highlight the need for caution in establishing a new dogma that human chronic liver disease and portal hypertension is reversible.

Keywords: Biomarker; Chronic liver disease; Cirrhosis; Hepatic circulation; Hepatic hemodynamic; Liver sinusoid; NAFLD; NASH; Portal pressure.

Conflict of interest statement

The author(s) declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Schematic representation of complications of portal hypertension. Clinically significant portal hypertension may lead to hepatic encephalopathy, gastroesophageal varices prone to hemorrhage, liver failure, hepatorenal syndrome and ascites and it is also associated with an increased risk for hepatocellular carcinoma development. GEV gastroesophageal varices, SBP spontaneous bacterial peritonitis
Fig. 2
Fig. 2
Main cellular mechanisms contributing to the progression of chronic liver disease in response to liver damage. Chronic liver injury induces the expression of cell adhesion molecules by LSEC, leading to a recruitment of macrophages to the tissue. These, together with liver damage, lead to necroinflammation, capillarization of LSEC, polarization of macrophages, HSC activation and liver fibrosis. aHSC activated hepatic stellate cell, cLSEC capillarized liver sinusoidal endothelial cell, dxHep dysfunctional hepatocyte
Fig. 3
Fig. 3
Stage-specific features determining the probability of regression of portal hypertension and chronic liver disease. It is accepted that the likeliness of regression is inversely correlated to the severity of the disease, usually determined by factors such as HVPG, thickness of fibrous septa or acellularization. HVPG hepatic venous pressure gradient, HE hepatic encephalopathy
Fig. 4
Fig. 4
Molecular mechanisms modulating regression of chronic liver disease. Regression of cirrhosis and portal hypertension is usually impaired by liver architecture (altered extracellular matrix and acellularization) and microcirculatory dysfunction. All these may induce an activation response to hepatic cells, promoting progression rather than regression of chronic liver disease. On the other hand, modulation of the phenotype of hepatic cells (green box) may inhibit said alterations and represent potential targets for regression of chronic liver disease. ECM extracellular matrix, HSC hepatic stellate cell, LSEC liver sinusoidal endothelial cell

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