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Therapeutic tools in portal hypertension: drugs

  • Conference paper
Book cover Portal Hypertension in the 21st Century

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Abstract

Portal hypertension often complicates the course of chronic liver disease and is a principal cause of mortality. Improvements in treating this complication made towards the end of the past century have been the consequence of several major achievements in our understanding of the pathophysiology of portal hypertension:

  1. 1.

    Increased intrahepatic vascular resistance (IHVR) to portal blood flow is the factor that initiates portal hypertension, but increased splanchnic blood flow due to splanchnic vasodilation contributes to maintain and aggravate this portal hypertension. Based on this finding, splanchnic vasoconstrictors are currently used to treat portal hypertension. As do beta-blockers, these reduce portal pressure, decreasing splanchnic blood flow.

  2. 2.

    In the cirrhotic liver, increased IHVR is the result of fixed elements (i.e. extracellular matrix, regenerative nodules, and vascular thrombosis) and elements that can be modulated (i.e. endothelial and stellate cells)1. Although the resistance provided by each of these modulatable and fixed elements is difficult to quantify precisely, vasodilators can reduce portal resistance up to 15% in the perfused cirrhotic rat liver2. This drop represents about 30% of the difference in resistance between the cirrhotic and normal liver. The dynamic component of the IHVR is a consequence of an enhanced vascular tone, secondary to an imbalance between vasoconstrictor and vasodilatory stimuli. Recent evidence indicates that a deficient intrahepatic release of nitric oxide (NO) plays a key role in the hepatic endothelial dysfunction of cirrhosis3, 4. In the normal liver the sinusoidal endothelial cells basally produce NO and increase its production in response to flow5, 6. In contrast, the cirrhotic liver fails to produce NO in response to incremental flow7. Endothelial(e)-NO synthase (NOS) and protein levels are unaltered, but endothelial-derived NO is impaired6. Since eNOS is extensively modified at the post-translational level, deficient NO release could be the consequence of an abnormality in one of these biochemical modifications occurring after injury to sinusoidal endothelial cells. For example, caveolin-l controls eNOS activity, and increased binding of caveolin to eNOS in cirrhosis is associated with reduced eNOS activity7. In addition, protein kinase B (Akt) phosphorylates eNOS and enhances its ability to generate NO. Down-regulation of Akt activity is responsible, in part, for the diminished NO production observed in cirrhotic livers, and constitutes another potential target for restoring hepatic endothelial function8. The hepatic vascular tone of the cirrhotic liver is also influenced by an increased production and exaggerated response to vasoconstrictors, such as endothelin-19, angiotensin II10, norepinephrine11–14, thromboxane and leukotrienes15, 16. Knowing that an increased intrahepatic vascular tone contributes toward increasing portal pressure has provided a rational basis for the use of vasodilators to treat portal hypertension.

  3. 3.

    The third important concept is the correlation between the value or change in portal pressure, as measured by the hepatic venous pressure gradient (HVPG), and clinical events (i.e. variceal formation and bleeding). Pharmacological or spontaneous reduction in portal pressure to below 12 mmHg, or more than 20% from baseline, leads to a null or low (10%) risk of variceal bleeding, respectively17–22. Pharmacological treatment seeks to achieve this reduction in portal pressure since it is known that this will lessen the risk of variceal bleeding and other complications of cirrhosis23. Non-response to vasoactive therapy is the most important independent risk factor for variceal bleeding23.

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Authors and Affiliations

  1. Department of Gastroenterology, Hospital Universitario Ramón y Cajal University of Alcalá, Ctra. de Colmenar, km. 9,100, 28034, Madrid, Spain

    Agustín Albillos

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  1. Agustín Albillos
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Editors and Affiliations

  1. Yale University School of Medicine, New Haven, CT, USA

    R. J. Groszmann

  2. Hepatic Hemodynamic Laboratory Liver Unit, Hospital Clinic, University of Barcelona, Spain

    J. Bosch

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Albillos, A. (2004). Therapeutic tools in portal hypertension: drugs. In: Groszmann, R.J., Bosch, J. (eds) Portal Hypertension in the 21st Century. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1042-9_20

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