Elsevier

Molecular Aspects of Medicine

Volume 29, Issues 1–2, February–April 2008, Pages 119-129
Molecular Aspects of Medicine

Review
Vasoactive factors and hemodynamic mechanisms in the pathophysiology of portal hypertension in cirrhosis

https://doi.org/10.1016/j.mam.2007.09.006Get rights and content

Abstract

Portal hypertension is primarily caused by the increase in resistance to portal outflow and secondly by an increase in splanchnic blood flow, which worsens and maintains the increased portal pressure. Increased portal inflow plays a role in the hyperdynamic circulatory syndrome, a characteristic feature of portal hypertensive patients. Almost all the known vasoactive systems/substances are activated in portal hypertension, but most authors stress the pathogenetic role of endothelial factors, such as COX-derivatives, nitric oxide, carbon monoxide. Endothelial dysfunction is differentially involved in different vascular beds and consists in alteration in response both to vasodilators and to vasoconstrictors. Understanding the pathogenesis of portal hypertension could be of great utility in preventing and curing the complications of portal hypertension, such as esophageal varices, hepatic encephalopathy, ascites.

Introduction

Portal hypertension is a hemodynamic syndrome mostly caused by liver cirrhosis in the Western Countries. It causes a series of alterations responsible for the onset of complications of cirrhosis, such as gastrointestinal hemorrhage, ascites, portal-systemic encephalopathy, hepato-renal syndrome, hepato-pulmonary syndrome, spontaneous bacterial peritonitis. Hemodynamic alterations of portal hypertension do not only involve portal–hepatic hemodynamics but splanchnic and systemic circulation too. Portal hypertension is defined as an increase in portal pressure above the normal range of 6–10 mm Hg or, considering the gradient between portal and hepatic veins, as assessed by hepatic vein catheterization, above 5 mm Hg. Portal hypertension is considered clinically relevant, i.e., capable of causing the development and rupture of esophageal varices, when the portal–hepatic gradient is above 10–12 mm Hg. The increase in resistance to outflow from the portal system, with the subsequent increase in portal pressure, causes the opening of portal-systemic collaterals. Portal-systemic shunts are responsible on the one hand for gastrointestinal hemorrhage (mostly due to the rupture of esophageal or gastric varices) and, on the other hand, they allow access to the systemic circulation of substances usually removed by the liver, which play a role in the pathogenesis of the hyperdynamic circulation, ascites and portal-systemic encephalopathy (Gatta et al., 1999).

Section snippets

Determinants of portal pressure

Portal pressure is the result of the relationship between the blood flow volume entering the portal system and the resistance to portal blood flow. The mathematical expression of this relationship is given by the Ohm’s formula: P = Q × R, where P represents change in pressure along the vessel, Q represents blood flow and R resistance to the flow. In normal liver, resistance is mainly located in terminal portal venules, in the sinusoids and in the roots of hepatic venules. The increase in resistance

Structural mechanical factors

The progressive deposition of collagen in the hepatic acini is the main mechanism responsible for the increase in resistance in cirrhosis. Collagen deposition in the Disse’s space narrows the sinusoidal lumen, and increases the distance between sinusoidal lumen and hepatocytes. The decrease in the total cross-sectional area of hepatic sinusoids causes an increase in resistance to portal flow. The further transformation of collagen into fibrotic tissue, together with regeneration of hepatocytes,

The forward-flow theory of portal hypertension

In normal liver, with normal resistance and compliance, an increase in flow do not modify portal pressure (Blendis, 1981). On the contrary, if the outflow portal resistance is increased, as in cirrhosis, an increase in portal flow is responsible for an increase in portal pressure (forward-flow theory of portal hypertension). In patients with portal hypertension, total splanchnic inflow is increased (Tisdale et al., 1959, Gitlin et al., 1970), as it was also shown in experimental models of

Conclusion

In recent years, the role of autocrine and paracrine endothelial factors in modulating hepatic vascular resistance and splanchnic blood flow has been highlighted in patients with portal hypertension. Vasoactive systems play a key role both in increasing sinusoidal resistance and in determining splanchnic arterial vasodilation thus contributing to the hyperdynamic circulatory syndrome. The same vasoactive system can play different role in different regional vascular beds. In particular, in

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