Osteopontin a Possible Therapeutic Target in Alcoholic Hepatitis
By Thomas R. Collins
Medscape Medical News
April 28, 2010 (Vienna, Austria) — New data from a Spanish research team suggest that the protein osteopontin, or its gene, might be a worthwhile target in therapy for patients with alcoholic hepatitis.
"We were able to identify osteopontin?.?.?. as one of the most upregulated genes in these patients, with a 58.5 value of overexpression vs normal livers," Oriol Morales, a PhD candidate at the University of Barcelona in Spain, told meeting attendees here at the European Association for the Study of the Liver (EASL) 45th Annual Meeting.
In their study of 44 patients with alcoholic hepatitis, the researchers found that osteopontin serum levels were about 5 times greater in alcoholic hepatitis patients than in healthy control subjects and about 4 times greater than in patients with hepatitis?C virus infection (P?< .001 in both cases).
They also found that osteopontin serum levels in patients with severe alcoholic hepatitis were double those of patients with less severe disease (P?= .038).
Osteopontin is a protein that is a prominent part of the extracellular matrices of bones and teeth. It is known for its ability to stimulate cell activity through multiple receptors.
Previous studies have established a relation between osteopontin and the liver. One showed that osteopontin expression in the liver was increased in chronically damaged livers. Another showed that mice lacking the osteopontin gene developed less hepatic injury. But a link to alcoholic hepatitis had not been explored.
The researchers also found that an ethanol-rich diet produced far more liver injury in wild-type mice than in osteopontin-knockout mice.
Female wild-type mice on an ethanol-rich diet had 4 times as much alanine aminotransferase (ALT), indicating liver injury, than mice lacking the osteopontin gene. Male wild-type mice had twice the ALT levels (P?< .05 in both cases).
"The results suggest that osteopontin-deficient mice could be protected from the cellular injury caused by ethanol," Mr. Morales said.
The researchers also found that osteopontin gene expression triggered the expression of profibrogenic genes.
Osteopontin could figure prominently in future treatment, Mr. Morales said. "Taken together, these results suggest that osteopontin could be a potential therapeutic target in patients with alcoholic hepatitis."
Mark Thursz, MD, professor of hepatology at Imperial College London in the United Kingdom, vice-secretary of EASL, and a moderator of the session, noted that osteopontin has already been drawing interest as a therapy for other illnesses, including rheumatoid arthritis.
"There is already some interest in it as a target for therapy," Dr. Thursz said. "It's difficult to say at this stage [of research]. There's this chicken and egg situation. Has it gone up because there's inflammation, or is it actually a cause of the inflammation?"
He said the study "gives some credence to the idea that this actually amplifies the inflammation and, therefore, by targeting it, you may have another therapeutic intervention in alcoholic hepatitis."
Any progress in treating the disease is sorely needed, he added, pointing out that there is a 30% mortality rate among patients with severe forms of the disease.
"At the moment all we have is steroids," Dr. Thursz said. "And one of the problems you have with steroids is you then put the patient at risk of infection. It's a very, sort of, blunderbus approach, frankly. You're just suppressing all the immune and inflammatory responses. We know patients with this disorder are susceptible to infection anyway, and then you make it worse by giving them steroids."
The study received no commercial financial support. Mr. Morales and Dr. Thursz have disclosed no relevant financial relationships.
European Association for the Study of the Liver (EASL) 45th Annual Meeting. Presented April?16, 2010.
