Therapy for portal hypertension: What is our pipeline?
Authors: Vijay Shah
Journal: Hepatology (2008)

Humankind has recognized the liver as a highly vascular organ, even since the Paleolithic Era.1 By 2000 B.C., many ancient civilizations came to recognize the link between ascites and liver disease.2 From this rich and long history was born the study of portal hypertension. In this context, it is quite remarkable that, at present, we still have no Food and Drug Administration–approved treatments for portal hypertension or any of its complications. Indeed, all of the currently-utilized therapies, including beta blockers, lactulose, and diuretics, are essentially used off-label to treat complications of portal hypertension. PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor. So what is our pipeline for future therapies in portal hypertension? The answer to this question is complex. Portal hypertension and its complications are often not appealing targets for drug development by pharmaceutical companies. Most companies have focused their efforts on the lower-hanging and more profitable fruits of viral hepatitis and liver cancer. However, this is not only a financial decision made by companies based on profits. Virology and cancer cell biology are far advanced in terms of their depth of molecular elucidation of these conditions. This has resulted in a rich pipeline of potential experimental therapeutics, which is being tapped by company research and development programs, which in turn, should lead to benefit for patients with these conditions. The science of portal hypertension is well grounded on physiologic and pathophysiologic principles3; for example, it is now well understood that portal hypertension results from an increase in intrahepatic resistance coupled with an increase in blood flow into the portal circulation.3 These mechanical principles are now indeed leading to the more in-depth basic investigations that are needed to expand the field,4-6 and may hopefully lead to the development of antibodies, small molecules, and other experimental therapeutics that could advance the treatment of portal hypertension. One of our best hopes for the development of new molecular targets for treatment of portal hypertension is the innate overlapping nature of this condition with a number of other non–liver related vascular diseases and conditions. Indeed, studying portal hypertension now requires a rigorous and thorough knowledge of cardiovascular pathophysiology and vascular biology, disciplines which have developed many targets for therapeutic successes in the cardiovascular arena over the past 25 years. Indeed, the use of beta blockers in portal hypertension derived directly from its use in patients with cardiac disease.7 Similarly, a number of therapies that are under current evaluation in portal hypertension came directly from the world of the cardiologist. For example, the statin class of medications is gaining a strong headwind as a potential therapy to reduce portal pressure by virtue of multiple mechanisms in complementary cell types, including endothelial cells and hepatic stellate cells, that culminate in increased intrahepatic nitric oxide signaling.8, 9 These effects are entirely independent of their lipid-lowering action for which these compounds are commonly used in patients today. Another burgeoning area that has emerged from the vascular field is the role of angiogenesis in portal hypertension. Although it is a complex process to regulate the formation and structure of new blood vessels and the role of this process in portal hypertension is not yet fully defined, a number of recent studies suggest that regulatory angiogenic molecules such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) may be one of the new frontiers for future therapy in portal hypertension, by correcting the altered sinusoidal, mesenteric, and collateral vessels that characterize portal hypertension.4, 6, 10 However, there is much to learn from other disciplines as well.4 For example, the small molecule receptor tyrosine kinase inhibitors, such as imatinib and sorafenib, that have pervaded the cancer field may also have promising effects on vascular cell biology as well. Recent studies have suggested that these agents interface in important ways with angiogenic and vasodilatory molecules such as VEGF, PDGF, and nitric oxide.11 Additionally, we need to interface with individuals with expertise in biomaterials. This may be the way that we can treat a vascular syndrome such as portal hypertension which has such protean but divergent phenotypes in different vascular beds, such as the splanchnic and intrahepatic circulations.3 This approach has been pursued in animals, though not yet successfully in humans, with the use of nitric oxide donors in a linker form with other carrier molecules.12 Perhaps delivery of nitric oxide donors in nanoparticles or other biomaterials that can be targeted to selective organs may be successful. Lastly, we need to continue our relentless pursuit of new molecular targets at the bench. This, too, will come with liver investigators standing side by side with our colleagues in other disciplines to allow us to gain from their expertise and enable us to translate knowledge and advance our mission of treating patients with portal hypertensive liver disease.