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Potential therapy reported for children, adults with end-stage liver disease

A Johns Hopkins Children's Center scientist reports success in animal studies in preventing a cascade of brain pathology that appears to both cause and signal the final and fatal stages of acute and chronic liver disease in children and adults. The findings ("Hyperammonemic Encepalopathy") appear in the May issue of Medicine.

In the review article, pediatric biochemical geneticist Saul Brusilow, M.D., writes that the chemical methionine sulfoximine (MSO) appears to prevent the brain swelling (encephalopathy) in patients with acute liver failure. It is the swelling, he believes, that causes pressure on the patient's brain, which leads to coma and ultimately death.

MSO is known to prevent the formation of glutamine, a by-product of high ammonia levels in the blood (hyperammonemia). Patients with advanced liver disease develop hyperammonemia as the failing liver can no longer process ammonia, a natural by-product in humans. "Interrupt glutamine formation and the swelling that follows and we might be able to prevent brain damage and death," says Brusilow.

Experimental evidence suggests that glutamine forms in one type of brain cell, the astrocyte. As glutamine accumulates, water also accumulates, causing the astrocyte to swell. It is this swelling, Brusilow theorizes, that puts pressure on the brain in acute liver failure, and interrupts the normal functions of the astrocyte; patients may then lapse into unconsciousness and death. Patients with chronic liver failure demonstrate the consequences of astrocyte swelling by exhibiting behavioral changes rather than brain swelling.

In their animal studies, Brusilow, emeritus professor of Pediatrics at Johns Hopkins, and his colleagues Richard Traystman, Ph.D., and Raymond Koehler, Ph.D., both in the Department of Anesthesiology and Critical Care Medicine, pretreated rats with MSO, then induced hyperammonemia. Compared to rats not pretreated, the test animals showed no swelling in either their a
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Contact: Wendy Mullins
wmullins@jhmi.edu
410-223-1741
Johns Hopkins Medical Institutions
13-May-2002


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