That’s the prediction from Thomas E. Starzl, MD, PhD, the clinician-researcher known to many as the “father of transplantation.” He “retired” in 1991 but remains active as Distinguished Service Professor of Surgery at the University of Pittsburgh School of Medicine, PA, where the Thomas E. Starzl Transplantation Institute is named in his honor.
On Sunday, Dr. Starzl delivered the annual AGA Morton I. Gossman Lectureship, which he titled “Anatomy of an Error.”
“Cadaver intestinal transplants could revolutionize the practice of gastroenterology in the same way that liver transplantation has revolutionized the practice of hepatology,” Dr. Starzl said. “The need clearly exists.”
Liver transplantation has become the standard of care for most patients with lethal hepatic disease, a prediction Dr. Starzl first published in The New England Journal of Medicine in 1989. But it could have become the standard of care years, possibly decades, earlier if clinician-researchers had questioned the accepted medical dogma of the day.
The delay in developing successful liver transplant procedures stems from two grave errors, Dr. Starzl suggested. The first error was the assumption that the amount of blood flow to the liver, not the source of the blood flow, is critical in maintaining hepatic homeostasis. The second error was the assumption that engraftment and rejection are not related to donor leukocytes. It took researchers more than three decades to put these two beliefs to experimental challenge and discover that both are wrong.
Dr. Starzl did much of the work to debunk them. He began by looking at experimental results in dogs with altered hepatic blood supply and reasoned that livers didn’t simply need a specific volume of blood, but blood from a specific source, the portal vein. His hypothesis was that portal blood is uniquely enriched with some unknown liver-supporting factor or factors that are not found in high concentration in blood from other sources. That hypothesis led him down two avenues of research: one uncovered the metabolic interactions of different abdominal organs, while the other led to human organ transplantation.
The metabolic question was solved first. Portal blood was found to have unique properties that affect lipid metabolism. Work in dogs eventually identified insulin as the first of several hepatotropic factors in portal blood.
But assuring portal blood supply was only half of the challenge. Rejection of alographic organ transplants was not recognized as an immune reaction until the 1950s and the role of graft leukocytes in rejection was not recognized until much later.
Pre-transplant irradiation and other immunosuppressive treatments showed early success in dogs, but human results were less positive. Early immunosuppression helped boost survival in kidney transplants, but liver transplants were not successful.
Dr. Starzl conducted a series of liver transplants in the early 1960s, but the patients died in less than a month. The problem was not overt rejection, but infection and widespread thrombi. Researchers in Europe had similar problems, leading to a worldwide moratorium on liver transplants.
Meanwhile, development continued in kidney transplantation. And when azathioprine emerged as an effective immunosuppressant, Dr. Starzl and others used the drug successfully in liver transplantation. But there were still reservations.
“Despite repeated success, the verdict was that liver transplantation was possible but not feasible,” Dr. Starzl said. “That changed with the appearance of cyclosporine.”
Of his first 14 liver transplant patients treated with cyclosporine plus and prednisone, 12 lived up to 14 months, a survival record. In 1983, an NIH consensus panel concluded that liver transplantation had become a clinical service rather than an experimental procedure.
Thirty years later, few clinicians are following an appropriate immunosuppression protocol, Dr. Starzl said. Decades of experimental work and clinical experience have shown that it’s possible to minimize, and sometimes eliminate immunosuppressants following transplantation if recipient immunosuppression begins before transplantation. Recipient pre-treatment with adjunct donor cells and immunosuppressive agents minimizes the need for post-transplant immunosuppression.
http://tristarpub.com/ddw2013/?p=141
No comments:
Post a Comment