By Judy Foreman, Globe Staff, 04/04/00

It is not a pretty way to die.

Every year, 2,000 Americans wind up in the emergency room hovering near death because their livers suddenly quit working.

Typically, they are healthy people who overdosed on acetaminophen (Tylenol) or other drugs, consumed large amounts of alcohol with Tylenol, ate poisonous mushrooms, or became acutely infected with the hepatitis-B virus.

Another 5,000 or so wind up in somewhat similar straits after years of battling cirrhosis, liver scarring often caused by alcoholism or hepatitis-C infection. Overall, 20 million Americans have some form of liver disease, and every year more than 25,000 die.

And, until recently, there were only two options for liver patients facing death from liver failure: A transplant from a cadaver - which means competing with 15,000 other patients for fewer than 5,000 livers. Or, for those with acetaminophen poisoning, a drug called Mucomyst, which, in some patients, can reverse liver damage if taken soon enough.

This paucity of options has nudged researchers to find new ways to buy time for desperately ill patients and make better use of available organs. At long last, these efforts are beginning to pay off, both in new, dialysis-type devices that can keep patients alive until a donor organ can be found or until their own livers regenerate, and better surgical approaches to transplantation itself.

The liver is one of the most complex organs in the body, with an astonishing ability to regenerate its cells. It helps process carbohydrates, fats and proteins. It makes the factors that help blood clot. It cleanses the blood of toxins.

And, whether it fails from a sudden drug overdose or after a long downhill slide, the results are catastrophic. Toxins build up all over the body, including the brain, which swells until it, too, shuts down, setting the patient up for infections, kidney failure and coma. Once a person is comatose, death often ensues within a few days.

But at the University of Chicago, Dr. Michael Millis, director of the liver transplant program, has already treated four patients with a new device called ELAD, or extra-corporeal liver assist device. Somewhat like a kidney dialysis machine, the ELAD artificial liver, made by the VitaGen Corp. in San Diego, takes over the functions of the patient's liver for up to seven days.

In theory, that's long enough for a donor liver to become available: Patients at the top of transplant lists often get a liver in three to four days. It's also enough time, in people with sudden liver failure, for the liver to partially heal.

With ELAD, a patient's blood is siphoned out of the body through filters containing cells taken from human liver cancer cell lines grown in the laboratory. Membranes in the ELAD device keep these cells from entering the patient's bloodstream, yet allow toxins to be removed from the patient's blood.

In Millis' study so far, three patients are alive and doing well; one patient, an 8-year-old boy with leukemia, died despite ELAD and a successful liver transplant.

At Massachusetts General Hospital, doctors and ethicists have just approved plans to test ELAD in 10 liver failure patients.

"It's a bridging strategy to get through acute liver failure," said Dr. Win Williams, director of interventional nephrology. "It could also be used in patients who are not transplantable, like victims of suicidal ingestions of drugs who might not be psychologically prepared or fit for liver transplantation."

But that's just the beginning.

At Circe Biomedical Inc., a Lexington-based firm, researchers have designed a device called HepatAssist that uses pig liver cells, not human cells, to filter blood. It's being tested in 100 patients at 19 centers in the United States and Europe, typically for six hours a day per patient, said bioengineer and company president Barry Solomon.

A few patients, Solomon said, have had enough regeneration of their own livers after a week of HepatAssist treatments that they no longer needed a transplant.

Another dialysis-like device, already approved by the US Food and Drug Administration and made by HemoTherapies Inc. in San Diego, uses a charcoal filter instead of cells to detoxify the blood in liver patients.

Other researchers, including a team at MGH, are experimenting with hepatocyte transplants - infusions of liver cells taken from a cadaver liver that would not be suitable for a full organ transplant. It's a promising approach, said Dr. Ray Chung, medical director of liver transplantation at MGH, though so far it's only been tried in about 50 people nationwide.

Ultimately, improvements in surgical techniques may save the most lives, especially living donor transplants, split liver transplants and "domino transplants" - all of which involve new ways of sharing limited donor tissue among more recipients.

In essence, Chung said, "a living donor transplant is creating a donor liver where there was none before." One piece of the liver is taken out of a healthy person and put into a recipient with a compatible blood type. If all goes well, the donor's own liver soon regrows to its former size, and the piece implanted into the recipient also grows to nearly full size.

"Living donors are the big rage," said Dr. Roger Jenkins, chief of liver surgery at the Lahey Clinic in Burlington, though so far they're a small part of the picture.

In 1998, only 72 of the 4,487 liver transplants in the United States involved living donors, according to the United Network for Organ Sharing, a nonprofit organization in Richmond, Va., that maintains transplant waiting lists.

Since 1989, most living donor transplants have been from an adult donor, often a parent, to a child. But increasingly, surgeons are trying adult-to-adult transplants. Doctors at Beth Israel-Deaconess Medical Center did the first such operation in New England last year, before switching to Lahey. Now, MGH is gearing up to do one.

It's a demanding procedure. Blood vessels and other structures in the donor's liver must be in the right places so "we can get it out safely," Jenkins said. "We may also have to say `no' [to a would-be donor] if the liver is too small."

For years, in fact, doctors weren't quite sure just how big a piece to take to keep a recipient alive. Now, they know that a recipient can get along until regeneration is completed on a piece of liver that is only about 1 percent of his body weight.

Ethically, living donor transplants are delicate as well. They involve "taking someone who's perfectly healthy and turning them into a sick patient," Jenkins said. Several living donors around the world have died, putting a burden on doctors to make sure donors are not pressured into the surgery.

Split liver transplants, which use cadaver livers, are simpler, although it still takes hours to divide a donated liver in a way that preserves blood vessels and bile ducts. In 1998, there were 138 split liver transplants in the United States, and the number is growing steadily.

In a split liver operation, a cadaver liver is divided so that the smaller, left lobe is given to a child or small adult, and the larger, right lobe is given to an adult.

In February, two MGH patients - 45-year old Larry Hause and 19-month old Jazymn Thompson Bordoy - each received a piece of one cadaver liver. It was only the second such operation in New England.

Equally ingenious is the "domino transplant" strategy, which is so new that the United Network for Organ Sharing doesn't even have figures on it.

In January, Lahey surgeons did the first two domino procedures in New England. It works like this: A patient with a potentially fatal but slow-developing liver problemcalled amyloidosis gets a healthy liver from a cadaver. The liver from the amyloidisis patient is then given to a patient whose liver is near failing anyway, extending his or her life with an organ that otherwise would have been discarded.

A domino transplant is not a perfect solution. But for Joseph Taylor, 53, a lawyer and youth worker with hepatitis C who lives in a Boston suburb and probably would not have survived the long wait on the transplant list, it was a gift from the gods.

"I was as happy as you could be," said Taylor, who was given the liver from an amyloidosis patient by Lahey surgeons in January. "I'm looking at life now, instead of death."

In the future, there will be other ways to save dying livers. Researchers at Dana-Farber Cancer Institute have found a promising technique that could one day help people with cirrhosis.

At the Massachusetts Institute of Technology, meanwhile, researchers have helped rats survive acute liver failure by injecting them with liver cells grown with a special technique in a laboratory dish.

In addition, researchers are looking for ways to capture and grow liver stem cells, the earliest liver cells from which all others spring. These cells could then be chemically triggered to regenerate the liver itself.

So far, none of these animal experiments is applicable to humans, cautioned Chung of MGH. "But they represent significant advances that could someday help patients."

SIDEBAR
PREVENTING LIVER DISEASE
More than 20 million Americans have liver diseases and more than 25,000 of them die each year. But some cases of liver disease are preventable. Here's how:

Vaccination can help prevent infection with the hepatitis B virus, which is spread by contact with blood and other bodily fluids and attacks the liver.

The risk of infection with the hepatitis C virus can be reduced by avoiding intravenous drug use, intranasal cocaine use, tattoos and unsafe sex.

Screening for genetic diseases such as hemochromatosis, or iron overload syndrome, may help prevent disease in genetically susceptible people. Hemochromatosis is a condition in which the body stores too much iron, sometimes leading to cirrhosis and liver cancer.

People should also avoid taking an overdose of acetaminophen - which can be as few as 20 extra-strength Tylenols - or using alcohol in combination with Tylenol. There are no firm guidelines on combining alcohol and Tylenol, but the rule of thumb is that if you are a regular Tylenol user, avoid heavy alcohol consumption.

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