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    California Pacific Currents 2000

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    New Techniques and Devices Are Revolutionizing Liver Transplantation and Therapy

    Robert Osorio, M.D.

    The ability to transplant an organ from one person to another has been a boon to medical practice, saving the lives of thousands who would have faced certain death just 40 years ago. Surgical techniques continue to improve, as have the medications used to combat transplant rejection. But there's a serious problem. Many more people need transplants than there are organs to transplant.

    For the physicians and scientists of California Pacific Medical Center's Liver Transplant Program, organ shortage is a constant worry. An estimated 15,000 patients nationwide need liver transplants, and only about 4,000 transplantable livers become available from brain-dead organ donors each year. Without liver function, a person cannot live.

    The liver performs many vital and complex functions, including manufacturing important proteins and other substances (bile, lipoproteins, clotting factors, etc.), cleansing toxins and waste products from the body, and metabolizing drugs absorbed from the digestive tract into forms the body can use.

    Unlike the tissue of many other organs, liver tissue — under the right conditions — will regenerate after damage or disease. This power to regenerate is the driving force behind new transplant techniques and promising research being done by the Liver Transplant Program.

    Innovative Transplant Options
    “Liver transplantation is no longer confined to cadaveric donor livers,” reports Robert Osorio, MD, surgical director of the Liver Transplant Program. People with liver disease can now be transplanted with portions of a liver (a graft) from a healthy living adult donor, provided the blood type of donor and recipient is compatible.

    In the most common of these living-donor procedures, the patient's diseased liver is removed and replaced with about a third of the living donor's liver. The transplanted piece of donor liver grows and remodels to form a complete liver after transplant. The donor's own intact liver in turn regenerates to form a complete liver. Both donor and recipient walk away with functioning livers.

    The technique is also sometimes used with cadaveric livers, maximizing their use so that one liver serves two recipients.

    Another technique is auxiliary liver transplantation. Similar to living-donor transplants, except that a smaller piece of donor liver is transplanted, this method is used in cases where only temporary augmentation of the recipient's liver function is needed until the native organ recovers and regenerates. After recovery, the donated liver section is removed, and the recipient goes on to lead a normal life.

    Liver Devices Offer New Hope
    Surgery in some cases, however, might be avoided altogether if a machine could do the work of an auxiliary graft, compensating for the damaged liver until it recovers and regenerates.

    This is the idea behind liver-assist devices, newly developed systems that, similar to kidney dialysis machines, clear toxins from the bloodstream, diminishing stress on the liver and allowing more time for liver recovery. California Pacific Medical Center's Liver Transplant Program is the first Northern California site to use the Liver Dialysis Unit™, the only liver-assist device approved by the FDA for hospital use. The device is especially useful for victims of drug toxicity or overdose.

    Liver assist devices, however, are only half a solution to a damaged liver. They clear toxins but do not perform the liver's other vital functions. Attention has turned to the creation of artificial liver systems that, positioned outside the body like a liver-assist device, would filter toxins as well as manufacture crucial biochemicals. Two artificial liver machines are currently in human clinical trials.

    In addition to filtering toxins, the two machines employ columns of cultured liver cells to produce biochemicals and perform other necessary liver activities. (One uses liver cells, hepatocytes, from pigs, and the other uses tumor cells, hepatomas, from human livers; although they are cancer cells, hepatomas can clean the blood and carry out other liver functions). Blood from the diseased liver patient is passed through the filters and columns of cells, reaping the benefits of toxin filtration and normal liver cell activity.

    That's the theory, at least. Early clinical trials with the two machines show marginal survival benefits, and their ability to replicate functions of the liver, other than filtering, is inconclusive. “The reason is that the number of cells used is about one-tenth the mass of cells needed,” says Robert Gish, MD, medical director of the Liver Transplant Program. “If the liver has a billion cells and you're only using 100 million, that's 900 million cells you don't have. Newer devices will have to have a much larger cell mass, or the cells will have to work more efficiently.”

    A Different Strategy
    Drs. Gish and Osorio, together with Dr. Sung-Soo Park of Ewha Womans University (Seoul, Korea), have taken matters into their own hands. They have established HepaHope, Inc., a company actively developing an artificial liver device they hope will overcome the cell mass problem. Rather than columns of cells, they are using multiple slices of pig liver tissue to up the volume of hepatocytes and other native porcine liver cells in their device.

    They first studied porcine livers, looking, for example, at how they clear toxins and the compatibility of pig liver products with humans. “There are a number of different tests to see how functional they are, how long they live, how well they function over time,” says Dr. Gish. The company is now testing the device on pigs with nonfunctioning livers, monitoring their vital signs, heart activity, intracranial pressure (crucial in acute catastrophic liver failure), and need for fluids, and evaluating their blood for toxins and the presence of beneficial liver proteins and other by-products.

    Safety Concerns
    But is it safe to filter blood using cells and organs from animals or hepatic tumor cells? Porcine livers are known to harbor retroviruses that are native to pigs but not found in humans. Could patients become infected with a pig retrovirus as a result of treatment? “In theory, yes,” says Dr. Gish, “but in trials with hundreds of people it has never been seen. We don't know if these viruses could be harmful to humans, but it is a concern.”

    And what about human hepatic tumor cells? Could a cell escape the machine and find its way into the patient's bloodstream, causing cancer? “That too has never been seen, but is a possible risk,” says Dr. Gish. (Normal, healthy human hepatocytes are not used in artificial liver systems because, unlike hepatic tumor cells, they are difficult to culture in quantity outside the body.) As with many medical advances, say Gish and Osorio, the potential risks must be weighed against the potential benefits of using the device.

    A Grueling Pace
    HepaHope expects to begin human trials within the year. In the meantime, Drs. Gish and Osorio have their hands full testing and perfecting the device, in addition to all the other work of the Liver Transplant Program. With worldwide epidemics of hepatitis B and C, the search for better therapies and a cure is urgent.