Endothelial dysfunction in cirrhosis: Role of inflammation and oxidative stress

Abstract

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.

Liver Disease as a Predictor of New‐Onset Atrial Fibrillation

“…Other potential mediators that share the common pathway of fibrosis and could play a role include transforming growth factor beta39 and connective tissue growth factor 40. Also, many inflammatory cytokines, such as interleukin‐6, interleukin‐8, and tumor necrosis factor‐alpha,41 and oxidative radicals, such as superoxides and peroxynitrite,42 are elevated in the setting of significant liver disease and also play a role in development of AF 43, 44, 45. Finally, many circulatory cytokines and neuropeptides that play a role in AF are upregulated by the autonomic dysfunction that occurs in liver disease 46…”

Review article: the role of the microcirculation in liver cirrhosis

“…In liver cirrhosis, marked changes occur within the intrahepatic microcirculation causing disruption to the normal regulatory mechanisms and ultimately leading to an increase in intrahepatic vascular resistance and portal hypertension . The rise in sinusoid resistance is due to both mechanical factors relating to microvascular structural changes, and dynamic factors including endothelial dysfunction, reduced NO production, increased release of vasoconstrictor products and contraction of HSC …”

“…In cirrhosis, NO levels in the intrahepatic microcirculation have been shown to be insufficient to prevent excessive vasoconstriction and increased hepatic vascular tone . The reduced bioavailability of NO is the hallmark of endothelial dysfunction and is due to decreased endothelial NO synthase (eNOS) activity resulting from oxidative stress, regulatory defects and increased level of eNOS inactivators . Although NO has been shown to be the primary molecule involved in vasodilation, there are number of other endothelial dilators identified to be deficient in cirrhosis and an increased release of vasoconstrictive mediators such as TxA2 and ET‐1 …”

“…Excessive splanchnic vasodilatation and splanchnic steal of blood causes homoeostatic stimulation of the RAAS, SNS and antidiuretic hormone leading to renal vasoconstriction. In addition, circulating inflammatory mediators may trigger endothelial dysfunction and microcirculatory dysregulation . The end result is a marked decrease in renal perfusion and glomerular filtration rate, renal tubular damage, increased serum creatinine concentration and ultimately HRS.…”

Insuficiencia hepática crónica y hemostasia

“…Estas vías desencadenan una disregulación del endotelio mediante la activación de la dimetilarginina asimétrica (ADMA), un inhibidor endógeno de la óxido nítrico sintetasa (eNOS) (16,17). Gracias a modelos animales, ahora se sabe que la disminución de la actividad de la eNOS es parte fundamental de la fisiopatología de la hipertensión portal (18,19).…”