• Hypertension, Portal/physiopathology
• Hypertension, Portal/etiology
• Humans
• Liver Cirrhosis/complications
• Liver Cirrhosis/physiopathology
• Esophageal and Gastric Varices/etiology
• Esophageal and Gastric Varices/physiopathology
• Esophageal and Gastric Varices/therapy
• Vascular Resistance/physiology
• Liver/physiopathology
• Liver/blood supply

• Cirrhosis of the liver
• Endothelial dysfunction
• Fibrosis
• Hepatic vascular resistance
• Portal hypertension

• Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
• University of Bern

• Cirrhosis
• Crosstalk
• HCC
• LSECs
• Liver fibrosis

• Carcinoma, Hepatocellular/pathology
• Endothelial Cells/pathology
• Hepatocytes/pathology
• Humans
• Liver/pathology
• Liver Cirrhosis/pathology
• Liver Neoplasms/pathology
• Tumor Microenvironment

During the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development.

The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.

• CLD
• HSC
• Kupffer cell
• LSEC
• NASH
• cirrhosis
• hepatocellular carcinoma
• portal hypertension

• nafld
• fxr
• bile acids
• microcholestasis

• Bile Acids and Salts/metabolism
• Homeostasis
• Humans
• Lipid Metabolism
• Liver/metabolism
• Non-alcoholic Fatty Liver Disease/drug therapy
• Non-alcoholic Fatty Liver Disease/metabolism
• Receptors, Cytoplasmic and Nuclear/metabolism
• Signal Transduction

• Belgium
• Georges Brohée
• hepato-gastroenterology
• research prize

Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated.

Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B₂, prostaglandin D₂ and prostaglandin E₂ were measured in the portal and the hepatic vein.

While the hepatic vein contained higher levels of thromboxane B₂ than the portal vein, levels of prostaglandin E₂ and D₂ were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B₂ in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D₂ and E₂ (all P<0.0001).

Elevated portal venous thromboxane B₂ concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis.

ClinicalTrials.gov identifier: NCT03584204.

• HVPG
• cirrhosis
• hepatic hemodynamic
• portal pressure
• sinusoid

• Instituto de Salud Carlos III

• Aorta
• Cyclooxygenase
• Liver injury
• Thioacetamide
• Vascular reactivity

• Pharmacologic prevention
• Portal hypertension
• Variceal bleeding

• Hepatic microcirculation
• Liver steatosis
• Liver-selective therapy
• V-PYRRO/NO

• angiogenesis
• farnesoid X receptor
• hepatic venous pressure gradient
• nitric oxide
• non-selective β-blockers
• portal hypertension
• renin–angiotensin–aldosterone
• statins

• contraction
• dihydroartemisinin
• farnesoid X receptor
• hepatic stellate cell
• portal hypertension

Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis.

Severe complications of liver cirrhosis are mostly related to portal hypertension. At the base of the pathogenesis of portal hypertension is the increase in hepatic vascular resistance to portal blood flow with subsequent development of hyperdynamic circulation, which, despite of the formation of collateral circulation, promotes progression of portal hypertension. An important role in its pathogenesis is played by the rearrangement of vascular bed and angiogenesis. As a result, strategic directions of the therapy of portal hypertension under liver cirrhosis include selectively decreasing hepatic vascular resistance with preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis, while striving to reduce the hepatic venous pressure gradient to less than 12 mmHg or 20% of the baseline. Over the last years, substantial progress in understanding the pathophysiological mechanisms of hemodynamic disorders under liver cirrhosis has resulted in the development of new drugs for their correction. Although the majority of them have so far been investigated only in animal experiments, as well as at the molecular and cellular level, it might be expected that the introduction of the new methods in clinical practice will increase the efficacy of the conservative approach to the prophylaxis and treatment of portal hypertension complications. The purpose of the review is to describe the known methods of portal hypertension pharmacotherapy and discuss the drugs that may affect the basic pathogenetic mechanisms of its development.

• Liver cirrhosis
• Portal hypertension
• Pathogenesis
• Medical therapy

• Animals
• Antihypertensive Agents/therapeutic use
• Humans
• Hypertension, Portal/diagnosis
• Hypertension, Portal/drug therapy
• Hypertension, Portal/etiology
• Hypertension, Portal/physiopathology
• Liver Circulation/drug effects
• Liver Cirrhosis/complications
• Liver Cirrhosis/diagnosis
• Portal Pressure/drug effects
• Risk Factors
• Treatment Outcome

• Acetates/therapeutic use
• Antioxidants/therapeutic use
• Biopterins/analogs & derivatives
• Biopterins/therapeutic use
• Chenodeoxycholic Acid/analogs & derivatives
• Chenodeoxycholic Acid/therapeutic use
• Cyclopropanes
• Endothelial Cells/drug effects
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Hypertension, Portal/drug therapy
• Hypertension, Portal/etiology
• Hypertension, Portal/physiopathology
• Leukotriene Antagonists/therapeutic use
• Liver Circulation/drug effects
• Liver Cirrhosis/complications
• Liver Cirrhosis/drug therapy
• Microvessels/drug effects
• Microvessels/physiopathology
• Molecular Targeted Therapy
• Naphthalenes/therapeutic use
• Neovascularization, Pathologic/drug therapy
• Propionates/therapeutic use
• Quinolines/therapeutic use
• Sulfides
• Vascular Resistance/drug effects

This review describes the recent developments in the pathobiology of endothelial dysfunction (ED) in the context of cirrhosis with portal hypertension and defines novel strategies and potential targets for therapy. ED has prognostic implications by predicting unfavourable early hepatic events and mortality in patients with portal hypertension and advanced liver diseases. ED characterised by an impaired bioactivity of nitric oxide (NO) within the hepatic circulation and is mainly due to decreased bioavailability of NO and accelerated degradation of NO with reactive oxygen species. Furthermore, elevated inflammatory markers also inhibit NO synthesis and causes ED in cirrhotic liver. Therefore, improvement of NO availability in the hepatic circulation can be beneficial for the improvement of endothelial dysfunction and associated portal hypertension in patients with cirrhosis. Furthermore, therapeutic agents that are identified in increasing NO bioavailability through improvement of hepatic endothelial nitric oxide synthase (eNOS) activity and reduction in hepatic asymmetric dimethylarginine, an endogenous modulator of eNOS and a key mediator of elevated intrahepatic vascular tone in cirrhosis would be interesting therapeutic approaches in patients with endothelial dysfunction and portal hypertension in advanced liver diseases.

• Asymmetric dimethylarginine
• Endothelial function
• Nitric oxide
• Portal hypertension
• Hepatic cirrhosis, Reactive oxygen species
• Inflammation

Variceal hemorrhage is a life-threatening complication of portal hypertension. Thus, prevention of variceal formation (pre-primary prophylaxis) or at least prevention of variceal bleeding are important goals to improve life quality and—if possible—survival of patients with liver cirrhosis. Interruption of the underlying cause of liver disease is the most successful approach, which, however, often fails. For this situation interruption or modulation of different pathophysiological mechanisms leading to fibrosis, hyperdynamic circulation and portal hypertension have been shown effective in animal models. But few could be translated to humans. By contrast, different steps to prevent first bleeding from varices have proven successful in many clinical trials. These applied mainly drugs to lower portal pressure, such as nonselective β-blockers, or endoscopic obliteration of varices, while prophylactic shunt procedures are not advised.

Reduced intrahepatic nitric oxide (NO) bioavailability and increased cyclooxygenase-1 (COX-1)-derived vasoconstrictor prostanoids modulate the hepatic vascular tone in cirrhosis. We aimed at investigating the reciprocal interactions between NO and COX in the hepatic endothelium of control and cirrhotic rats. NO bioavailability (DAF-FM-DA staining), superoxide (O₂⁻) content (DHE staining), prostanoid production (PGI₂ and TXA₂ by enzyme immunoassays) as well as COX expression (Western Blot), were determined in hepatic endothelial cells (HEC) from control and cirrhotic rats submitted to different experimental conditions: COX activation, COX inhibition, NO activation and NO inhibition. In control and cirrhotic HEC, COX activation with arachidonic acid reduced NO bioavailability and increased O₂⁻ levels. These effects were abolished by pre-treating HEC with the COX inhibitor indomethacin. In control, but not in cirrhotic HEC, scavenging of O₂⁻ by superoxide dismutase (SOD) incubation partially restored the decrease in NO bioavailability promoted by COX activation. NO supplementation produced a significant and parallel reduction in PGI₂ and TXA₂ production in control HEC, whereas it only reduced TXA₂ production in cirrhotic HEC. By contrast, in control and cirrhotic HEC, NO inhibition did not modify COX expression or activity. Our results demonstrate that NO and COX systems are closely interrelated in HEC. This is especially relevant in cirrhotic HEC where COX inhibition increases NO bioavailability and NO supplementation induces a reduction in TXA₂. These strategies may have beneficial effects ameliorating the vasoconstrictor/vasodilator imbalance of the intrahepatic circulation of cirrhotic livers.

Portal hypertension (PHT) is defined as a pathological increase in portal venous pressure and frequently accompanies cirrhosis. Portal pressure can be increased by a rise in portal blood flow, an increase in vascular resistance, or the combination. In cirrhosis, the primary factor leading to PHT is an increase in intra-hepatic resistance to blood flow. Although much of this increase is a mechanical consequence of architectural disturbances, there is a dynamic and reversible component that represents up to a third of the increased vascular resistance in cirrhosis. Many vasoactive substances contribute to the development of PHT. Among these, nitric oxide (NO) is the key mediator that paradoxically regulates the sinusoidal (intra-hepatic) and systemic/splanchnic circulations. NO deficiency in the liver leads to increased intra-hepatic resistance while increased NO in the circulation contributes to the hyperdynamic systemic/splanchnic circulation. NO mediated-angiogenesis also plays a role in splanchnic vasodilation and collateral circulation formation. NO donors reduce PHT in animals models but the key clinical challenge is the development of an NO donor or drug delivery system that selectively targets the liver.

• Nitric oxide
• Portal hypertension
• Hepatic stellate cell
• Liver cirrhosis

• Animals
• Antihypertensive Agents/pharmacology
• Humans
• Hypertension, Portal/drug therapy
• Hypertension, Portal/etiology
• Hypertension, Portal/metabolism
• Hypertension, Portal/physiopathology
• Liver Cirrhosis/complications
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/physiopathology
• Nitric Oxide/metabolism
• Nitric Oxide Donors/pharmacology
• Nitric Oxide Synthase/metabolism
• Portal Pressure/drug effects
• Portal Vein/drug effects
• Portal Vein/metabolism
• Portal Vein/physiopathology
• Signal Transduction
• Splanchnic Circulation

The concept of acute-on-chronic liver failure (ACLF) was introduced recently to describe a subset of patients with chronic liver disease presenting with profound deterioration of liver function and rapidly evolving multi-organ failure. ACLF is frequently accompanied by the development of severe inflammatory response syndrome and has a high mortality. To date, treatment options are limited and exclusively supportive. Over the last few years, some insights have been generated in the pathophysiology of ACLF. A key role for the interaction of innate immune dysfunction, enhanced bacterial translocation from the gut, and circulatory dysfunction has been proposed. In this respect, therapeutic strategies have been examined, with variable success, in experimental studies in animals and humans. This review focuses on potentially relevant pathophysiological elements in the development of ACLF and points out promising treatment modalities in ACLF.

The NO - cGMP system plays a key role in the regulation of sinusoidal tonus and liver blood flow with phosphodiesterase-5 (PDE-5) terminating the dilatory action of cGMP. We, therefore, investigated the effects of PDE-5 inhibitors on hepatic and systemic hemodynamics in rats.

Hemodynamic parameters were monitored for 60 min. after intravenous injection of sildenafil and vardenafil [1, 10 and 100 μg/kg (sil1, sil10, sil100, var1, var10, var100)] in anesthetized rats.

Cardiac output and heart rate remained constant. After a short dip, mean arterial blood pressure again increased. Systemic vascular resistance transiently decreased slightly. Changes in hepatic hemodynamic parameters started after few minutes and continued for at least 60 min. Portal (var10 -31%, sil10 -34%) and hepatic arterial resistance (var10 -30%, sil10 -32%) decreased significantly (p < 0.05). At the same time portal venous (var10 +29%, sil10 +24%), hepatic arterial (var10 +34%, sil10 +48%), and hepatic parenchymal blood flow (var10 +15%, sil10 +15%) increased significantly (p < 0.05). The fractional liver blood flow (total liver flow/cardiac output) increased significantly (var10 26%, sil10 23%). Portal pressure remained constant or tended to decrease. 10 μg/kg was the most effective dose for both PDE-5 inhibitors.

Low doses of phosphodiesterase-5 inhibitors have distinct effects on hepatic hemodynamic parameters. Their therapeutic use in portal hypertension should therefore be evaluated.

• Cardiovascular System/physiopathology
• Drug Design
• Humans
• Hypertension, Portal/drug therapy
• Hypertension, Portal/physiopathology
• Liver/physiopathology
• Neovascularization, Pathologic
• Platelet-Derived Growth Factor/physiology
• Vascular Endothelial Growth Factor A/physiology

Intrahepatic vascular resistance augmentation and portal blood flow increase are main mechanisms of portal hypertension. The former as an initial factor is mainly due to liver structure changes and motivity changes (reversible). It has been demonstrated that this reversible resistance can be reduced by 20%-30% with drugs. Portosystemic shunt or transjugular intrahepatic portosystemic shunt (TIPS) may induce many severe complications such as hepatic encephalopathy and stent re-obstruction. Therefore, researchers have performed plenty of experimental investigations about drug treatment of portal hypertension, and this article introduces their new advances in this field.

• Portal hypertension
• Drug
• Treatment

• hepatic stellate cell
• contraction
• fibrosis
• pericyte
• rho-associated kinase
• sinusoid