Doctors have identified the underlying origins behind portal hypertension, a serious form of high blood pressure in the liver related to liver disease. Their study is reported online at the website of the science journal Nature Medicine.1
Compromised Bloodflow
Portal hypertension is high blood pressure in the portal vein, which feeds blood to the liver. This blood vessel provides about three-quarters of the liver's blood supply. In the industrialized world, liver cirrhosis far outnumbers the various causes of portal hypertension. Since this form of liver scarring distorts the structure of the liver, the organ's blood vessels, too, become distorted and compressed, making it harder for blood to flow through them. In alcoholic liver disease (ALD), liver cells can swell, which is also a contributing factor to portal hypertension.2
There are no symptoms of this condition, but it can manifest itself in the form of other conditions, such as acute internal bleeding. Encephalopathy (a degenerative condition of the brain) and ascites (fluid build-up in the liver) are also associated with portal hypertension.2
Intervening at the Molecular Level?
In this study, Don Rockey, MD, chief of the Digestive and Liver Diseases Section at UT Southwestern Medical Center in Dallas, identified the cellular activity that results in portal hypertension. He and his team then took their research a step further, showing that if the underlying process can be blocked, the hypertension can subside.
"Portal hypertension is a deadly disease that complicates many forms of chronic liver injury," said Rockey, who was a professor of Gastroenterology and director of the Liver Center at Duke University when he participated in this research. "When this occurs in its most severe form, the prognosis definitely becomes guarded." It's at this point that patients are considered for a liver transplant, he said.
Portal hypertension can also be potentially deadly, with an approximate 30% mortality rate, the researchers pointed out. Thus, the findings of this study have possible clinical implications, such as forming a foundation for strategies to prevent the condition in people with liver disease.
"The end result of portal hypertension is bleeding and development of ascites," Rockey said. "So, if you could treat it early, you could prevent [that]."
Why Don’t Blood Vessels Stay Open?
According to earlier research, portal hypertension at the cellular level results from the reduced production of nitric oxide, a substance that regulates the widening of blood vessels.3,4
The latest study by Rockey and his colleagues discovered how nitric oxide production breaks down when portal hypertension occurs. They found that a protein known as GRK2 drives the reduced production of the vessel-widening compound by attaching to another protein known as AKT. When these two proteins lock with each other, nitric oxide production diminishes.
"We've shown that the endothelial cells that line the blood vessels in the liver don't work quite right," Rockey stated. "Specifically, they don't produce nitric oxide."
"The problem is that there are a number of signaling pathways that are disrupted, and that results in the reduced production of nitric oxide," he said. (The term "signaling pathways" describes a series of processes that result in a particular event in the body. The event is triggered by a certain chemical signal).
Blocking a Protein May Help
Once Rockey's group learned the origins of nitric oxide breakdown, they then were able to confirm that reducing production of GRK2 in turn restored AKT production, and helped restore levels of nitric oxide. In experiments with mice, the team learned that reducing GRK2 normalized portal blood pressure in the livers of the animals, and these mice "developed less severe portal hypertension" than mice that maintained levels of GRK2.
In the meantime, more research will be needed, he said, to determine how to control GRK2 proteins that interfere with AKT production with the aim of maintaining levels of nitric oxide.
1. Liu S, Premont RT, Kontos CD, Zhu S, Rockey DC. A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension. Nat Med 2005 Sep;11(9):952-8. Epub Sep 4.
2. Beers MH, Berkow R, Bogin RM et al. Portal Hypertension. In: The Merck Manual. 17th ed. Merck Research Laboratories: Whitehouse Station, NJ;358-61.
3. Fiorucci S, Antonelli E, Morelli A. Nitric oxide and portal hypertension: a nitric-oxide-releasing derivative of ursodeoxycholic acid that selectively releases nitric oxide in the liver. Dig Liver Dis 2003 May;35 Suppl 2:S61-9.
4. Gonzalez-Abraldes J, Garcia-Pagan JC, Bosch J. Nitric oxide and portal hypertension. Metab Brain Dis 2002 Dec;17(4):311-24.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
