JHU Med 2002-44 (treatment for end-stage liver disease)

[Dennis O'Shea]

Johns Hopkins Medical Institutions
Office of Communications and Public Affairs
Johns Hopkins Children's Center
Media Contact: Wendy Mullins
410-223-1741
E-mail: wmullins@jhmi.edu
May 14 2002

FOR IMMEDIATE RELEASE

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 
astrocytes or brains, and none showed signs of brain damage.

It's well known that patients with end-stage liver disease are 
hyperammonemic and have swollen astrocytes and increased levels of 
glutamine, Brusilow notes. He plans to begin clinical trials of MSO in such 
patients within a year.

Brusilow is widely regarded for his research on and the treatment of 
patients with a rare biochemical defect known as urea cycle disorder, which 
has some of the earmarks of the ammonia toxicity and brain pathology that 
characterize end-stage acute and chronic liver disease. In 1992, he 
developed the first and only successful treatment for urea cycle disorder, 
which uses the drug Buphenyl to prevent the buildup of excess ammonia, and 
thus prevents glutamine formation in the brain.

The study was funded by the National Institute of Child Health and the 
National Institute of Neurologic Diseases.

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