Korean J Gastroenterol.  2010 Sep;56(3):144-154. 10.4166/kjg.2010.56.3.144.

Treatment Update on Portal Hypertension and Complications

• Lee JW

• KMID: 948777
• DOI: http://doi.org/10.4166/kjg.2010.56.3.144

Abstract

Current understanding of the pathophysiology of portal hypertension has resulted in therapeutic approaches aimed at correcting the increased splanchnic blood flow and some of which have been already used in clinical practice. Recently new perspectives opened and erstwhile paradigm has been changed to focus on increased resistance to portal blood flow and the formation of portosystemic collateralization. Several studies revealed the clear-cut mechanisms of hepatic endothelial dysfunction and abnormal angiogenesis contributing to the development of portal hypertension. Thus the modulations of hyperdynamic circulation or angiogenesis seem to be valuable therapeutic targets. In the current review update, we discuss the multidisciplinary management of modulating hepatic vascular resistance and abnormal angiogenesis associated with portal hypertension. However, these new pharmacological approaches are still under investigation and widescale clinical application are needed to develop effective strategies.

Keyword

Portal hypertension; Intrahepatic resistance; Endothelial dysfunction; Angiogenesis

MeSH Terms

Adrenergic beta-Antagonists/therapeutic use
Bone Marrow Transplantation
Cyclooxygenase Inhibitors/therapeutic use
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
Hypertension, Portal/*therapy
Neovascularization, Pathologic/drug therapy
Nitric Oxide/metabolism
Vascular Resistance
Vasoconstrictor Agents/therapeutic use

Figure

• 

  Fig. 1. New paradigm for the treatment of portal hypertension. Current treatments are based on the use of drugs that decrease blood flow by attenuating the splanchnic vasodilatation (old paradigm), but new treatments aim at correcting the increased hepatic vascular resistance and the formation of portal-systemic collaterals. (modified from Bosch et al., J of Hepatology 2010).

• 

  Fig. 2. Mechanisms mediating the decrease in hepatic resistance by statins. Statins increase eNOS expression and activity. The most immediate effect of statins on endothelial NO production is an increase in eNOS phosphorylation, with subsequent increased activity. This is mediated by the activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway that leads to an increase in Akt phosphorylation with ensuing eNOS phosphorylation. Statins reduce the expression of the eNOS inhibitory protein caveolin-1 and increase the interaction of eNOS with its stimulatory protein Hsp90. These effects occur slower than the PI3K/Akt pathway activation. Statins also increase the expression of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme for de novo synthesis of tetrahydrobiopterin (BH4), a cofactor that increases eNOS activity by preventing eNOS uncoupling and, thus, superoxide generation. Statins also upregulate eNOS expression by increasing eNOS mRNA stability. Lastly, statins inhibit hepatic RhoA/Rho kinase signalling, which increases eNOS expression and decreases hepatic stellate cell (HSC) contractility (modified from Bosch et al., J of Hepatology 2010).

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  Fig. 3. Double-blind randomized controlled trial of simvastatin vs. placebo for portal hypertension in patients with cirrhosis. (A) HVPG decreased significantly in patients receiving simvastatin, but not in those receiving placebo. (B) In the group of patients treated with simvastatin, the decrease in portal pressure was observed both in patients under no treatment and in patients under continuous propranolol administration, suggesting an additive effect with non-selective beta-blockers (modified from Abraldes et al., Gastroenterology 2009). HVPG, hepatic venous pressure gradient.

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  Fig. 4. Tetrahydropiopterin (BH4) is an essential cofactor for eNOS. Decreased BH4 levels in the cirrhotic liver determine eNOS uncoupling, which results in decreased NO synthesis and increased release of superoxide radicals, which in turn can react with NO, further decreasing the bioavailability of NO. NO, nitric oxide; eNOS, endothelial nitric oxide synthase.

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  Fig. 5. Percentage change in HVPG divided by Child Pugh status using individual patient data from three ARB/ACEi versus BB studies. As calculated from individual patient data, the HVPG reduction in patients with Child Pugh A cirrhosis receiving ARB/ACEi's (−17%) was similar to those with Child Pugh A cirrhosis receiving beta-blockade (−21%) and greater than those patients with Child Pugh B/C cirrhosis receiving ARB/ACEi's (3%). The mean percentage change and the 95% confidence limits are represented. (modified from Tandon et al., J of Hepatology 2010). HVPG, hepatic venous pressure gradient; ARB, Angiotensin receptor blocker; ACEi, Angiotensin converting enzyme inhibitor; BB, beta blocker.

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