The liver transplant: “a tricky, tricky thing”

Abstract

“Impossible is nothing”, said Muhammad Ali, the boxer who spent much of the 1960s fighting battles in and out of the ring. It was a feeling that pervaded the decade: from the social reform that embroiled Ali to the iconic scientific achievements of the time—most notably the moon landing but, more significantly in the long run, the first liver transplantation. The human kidney had been successfully transplanted in 1954 setting the 1960s up to be the decade of the liver. It would not be easy. “The liver transplant was a tricky, tricky thing”, says Thomas Starzl, the now-retired physician from the University of Pittsburgh, PA, USA, who was the first to successfully transplant a liver. “They said that it could not be done.” Unlike with the kidney, there was no equivalent of the dialysis machine to keep patients alive without a liver. The organ's double blood supply further complicated maintenance of circulation during the operation. Starzl spent much of the turn of the decade experimenting with dogs. “I did around 50 experiments with no animal lasting longer than a few hours before I began to succeed”, he says. “The solution in the end was a mechanical one—to reroute the blood from the bottom half of the body to the top. That way we could avoid the high venous pressure that would damage the organs in the lower half during the hour or so it took me to stitch the new liver in.” If war is the engine room of scientific discovery—the space race a side-show to the cold war, organ transplantation first systematically studied to treat wounded World War 2 pilots—then science fiction is its captain. It helped steer Starzl through choppy waters. His father, Roman Frederick Starzl, is regarded as one of the fathers of modern science fiction. “He was a marvellous man”, remembers Starzl, “always inventing machines and devices. One of his stories quite accurately predicted the moon landing. He really made me believe that anything was possible.” Starzl and his colleagues needed that self-belief: turning science fiction into science fact was a bloody affair. All early attempts at organ transplantation were followed by wary mutterings of Dr Frankenstein and ungodly meddling, liver transplants in particular were targeted for using too much blood. The leap from animal to man was proving tough. “The patients that we were getting were already at death's door”, says Starzl, “and the diseased liver presents its own issues.” At the later stages of disease, portal hypertension leads to the forming of collateral vessels that bypass the liver, cocooning the organ behind a series of delicate tripwires. Add to that the fact that a diseased liver does not sufficiently produce the coagulation factors normally relied on during surgery, meaning that cuts in a patient with liver disease can cause abnormal, life-threatening bleeds. In 1963, Starzl attempted five human liver transplants. The first bled to death on the operating table, and none of the other four lived beyond 23 days, dying from pulmonary embolisms and infections. “We'd failed”, says Starzl who that year called a moratorium on liver transplants. “We needed better control of infections, better management of mechanical surgical problems, and, as a highest priority, we needed better ways of controlling rejection.” Help came from across the Atlantic from Sir Roy Calne, Professor Emeritus of Surgery, University of Cambridge in the UK. In 1959, during his time at the Royal College of Surgeons in England, he'd discovered that highly lethal total-body radiation did not prolong kidney graft survival, but that, given to dogs, the anti-leukaemia drug mercaptopurine did. “We still needed something better”, says Calne, “so Peter Medawar [the immunologist who discovered acquired immune tolerance] suggested I go to America to look at other compounds.” At Harvard Medical School, Calne was given candidate drugs by Nobel laureates George Hitchings and Gertrude Elion, who had developed mercaptopurine. “One of them, azathioprine, turned out to be a little better than mercaptopurine.” Azathioprine, mixed with prednisone, worked well during kidney transplants and, added to the knowledge of human leukocyte antigen and an improved ability to match tissue to a recipient led Starzl to call off his moratorium. He did the first successful liver transplant in 1967. Calne did the first in Europe shortly after in 1968. Successive improvements by the two scientists in avoiding and understanding rejection followed, though none, says Starzl, “compared with the importance of ciclosporin, introduced by Roy in 1967.” Calne had seen impressive results with ciclosporin in animals. “So I went to the company that made it and said we want to use it for people and they said ‘no, there's no market for it’”, remembers Calne. Luckily, they eventually relented. “They said ‘fine, but you know we're going to lose money on this?’” They were wrong. The drug improved kidney graft survival from 50% to 80%. Within 2–3 years after its introduction the number of centres doing organ transplantation went from about ten to thousands. “It was a watershed moment”, says Calne. “It helped transplantation become more respectable.” Today, with more than 25 000 livers being successfully transplanted every year, and with many of the techniques pioneered for this tricky organ used to improve the transplantation of others, the quest to transplant the human liver was certainly a moon-shot worth taking.