Advances in therapeutic options for portal hypertension

Abstract

Portal hypertension represents one of the major clinical consequences of chronic liver disease, having a deep impact on patients' prognosis and survival. Its pathophysiology defines a pathological increase in the intrahepatic vascular resistance as the primary factor in its development, being subsequently aggravated by a paradoxical increase in portal blood inflow. Although extensive preclinical and clinical research in the field has been developed in recent decades, no effective treatment targeting its primary mechanism has been defined. The present review critically summarizes the current knowledge in portal hypertension therapeutics, focusing on those strategies driven by the disease pathophysiology and underlying cellular mechanisms.

Keywords: HVPG; cirrhosis; hepatic hemodynamic; portal pressure; sinusoid.

Figure 1.

Schematic representation of different therapeutic approaches for portal hypertension focused on their liver vasomodulation effect. Drugs in bold denote currently ongoing RCT and known mechanisms of action are indicated in parenthesis. APAP, acetaminophen; COX, cyclooxygenase; ECA, enzyme converter of angiotensin; ERβ, estrogen receptor beta; FXR, farnesoid X receptor; OCA, obeticholic acid; 5-MTHF, 5 methylfolate; eNOS, endothelial nitric oxide synthase; ET, endothelin receptor; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; KLF2, Kruppel-like factor 2; NO, nitric oxide; sGC, soluble guanylate cyclase; L-arg, L-arginine; LTC, leukotriene; MAS, Mas receptor; PDE, phosphodiesterase; NCX, NO-donor compound derived from ursodeoxycholic acid; JNK, Jun N-terminal kinases; PLA2, phospholipase A2; RhoK, Rho kinase; RAA, renin–angiotensin–aldosterone; RCT, randomized controlled trial; TXA2, thromboxane A2.

Figure 2.

Schematic representation of different therapeutic approaches for portal hypertension based on their effect on apoptosis, oxidative stress or inflammation as main features of chronic liver damage. Known mechanisms of action are indicated in parenthesis. ASK1, apoptosis signal-regulating kinase; CeO₂, cerium oxide; EET, epoxyeicosatrienoic acids; GLP-1R, glucagon-like peptide 1 receptor; JAK2, janus kinase 2; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; rMn, Recombinant Manganese; ROS, reactive oxygen species; SOD, superoxide dismutase.