Transcribo a continuación el artículo tal y como ha sido publicado en dicha revista como mi homenaje particular a dichos pioneros y para servir de introducción a los alumnos que deseen conocer cómo comenzó el trasplante hepático.
The history of medicine is that what was inconceivable yesterday and barely achievable today often becomes routine tomorrow .1
Little more than a generation ago, treatment options for endstage liver disease were few and of limited durable utility. Little could be done to stem the decline of affected patients, who would ultimately go on to have liver failure and portal hypertension — variceal bleeding, intractable ascites, peritonitis, jaundice, hepatic encephalopathy,and coagulopathy —culminating in multisystem failure.
All that changed in 1983, when successes in experimental liver transplantation justified the procedure’s generalization as standard treatment. In a tribute to the pioneers who shepherded liver transplantation from barely imagined concept to fully implemented reality, the 2012 Lasker–DeBakey Clinical Medical Research Award honors Thomas Starzl of the University of Pittsburgh and Roy Calne of Cambridge University. Together, these physician-scientists bridged an intellectual and technical chasm as wide and forbidding as the ocean that separated them.
The era of solid-organ transplantation was inaugurated in 1954 with a successful kidney transplantation between identical twin brothers. But while nascent approaches to immunosuppression permitted renal transplantation to flourish, early efforts at liver transplantation stagnated, despite observations in pigs and dogs suggesting that the liver might be an “immunologically privileged” organ. Preliminary work on experimental canine liver transplantation was reported initially in the 1950s, heralding a disappointing foray into auxiliary liver transplantation (insertion of a donor liver without removal of the native liver), after which orthotopic liver transplantation (replacement of the native liver by the donor liver; see illustration) gained traction.2
By the early 1960s, in the laboratories of Starzl, then at the University of Colorado, and Calne, at Cambridge, acquisition of the technical expertise for replacing the liver and the availability of early-generation immunosuppressive drugs converged, setting the stage for success in experimental animals, followed by Starzl’s first attempted human liver transplantation in 1963.1,2 The recipient, a 3-year-old boy with biliary atresia, bled to death on the table. In the ensuing year, Starzl tried five more times, but none of the recipients— or two others elsewhere — survived longer than 23 days. Although these early deaths were not attributed to rejection, poor initial graft function resulting from ischemic damage, in concert with limited options for immunosuppression (azathioprine and prednisone), led to what appeared to be insurmountable obstaclesof uncontrolled coagulopathy, infection, and multiorgan failure. Accordingly, a nearly 4-year moratorium on liver transplantation followed.2
After the clinical introduction of antilymphocyte serum in 1966, Starzl was emboldened to try again, and in 1967, he performed the first successful human liver replacement in a 19-month-old girl with liver cancer. She survived for 13 months, only to die of metastatic disease.2 In 1968, Calne performed the first human liver transplantation in Europe, and from the late 1960s to the mid-1970s, because few others had had success or gained any confidence in the procedure, Starzl and Calne were the only ones pursuing liver transplantation in earnest. In the 1970s, they were joined by fledgling programs in Europe. Even with the use of immunosuppressive agents such as azathioprine, prednisone, and antilymphocyte serum, the rate of 1-year survival remained below 20% through much of the 1970s.
Because the procedure was so fraught with danger and its record so poor, liver transplantation was reserved as a last-ditch, heroic intervention for patients with no other options.
Despite these inauspicious beginnings, a series of developments contributed incrementally to liver transplantation’s success. Before 1968, organs were procured only from donors whose hearts had stopped. During the interval between cardiac death and organ harvesting, ischemia compromised donor-organ viability and function. In 1968, however, the concept of brain death was accepted.3 One consequence was that, for the first time, organs could be removed from donors after death determined by absence of brain activity but with preserved cardiorespiratory function, which led to marked improvement in early allograft function. Still, during the 1970s, 70% of liver-allograft recipients died shortly after surgery.
Then, in 1979, Calne reported the successful application of the calcineurin inhibitor cyclosporine to organ transplantation.4 The availability of this more selective T-cell inhibitor revolutionized transplantation. In Starzl’s experience, among 170 liver-transplant recipients treated between 1963 and 1979 with “conventional immunosuppression,” 1-year survival was 33%, whereas 11 of the first 12 liver-transplant recipients treated with cyclosporine in 1979–1980 survived more than a year,2 as did 70% of 40 recipients treated with cyclosporine in 1980–1981 (by which time Starzl was at the University of Pittsburgh). This was the inflection point.
By 1983, results were sufficiently convincing for a National Institutes of Health Consensus Development Conference to conclude that liver transplantation should be considered an accepted, clinically applicable, lifesaving procedure (http://consensus.nih.gov/1983/1983livertransplantation036html.htm).2 Along the way, Starzl’s and Calne’s successes enticed scores of other surgical teams to take up the mantle, and progress accelerated.
In addition to refinements in operative procedure and management of intraoperative physiological derangements, evolving immunosuppressive regimens (e.g., monoclonal antibodies to T cells and the more potent calcineurin inhibitor tacrolimus) allowed physicians to fine-tune the delicate balance between immunologic suppression and avoiding the risk of life-threatening infection. Other improvements in liver transplantation resulted from advances in organ procurement, preservation, and allocation. As its success rate increased, liver transplantationwas no longer considered “so drastic that it was used only as a last resort.”5
Instead, application of the procedure expanded to include and even favor healthier recipients, earlier in the course of disease. Better patient selection and timing may have contributed more to the success of liver transplantation than did many technological advances. But as the procedure became mainstream, indications expanded progressively, as conditions that had been relative and even absolute contraindications to the procedure in the early days fell by the wayside (e.g., hepatitis B, alcohol or substance abuse, hepatocellular carcinoma, advanced age, portal-vein thrombosis, prior abdominal surgery, or HIV infection).5
Many other dividends accrued from progress in liver transplantation
— advances in understanding of liver physiology, genetically determined disorders involving the liver, transplantation immunology and tolerance, and the ethics and equity of organ donation and distribution. Certainly, nothing did more than the expansion of liver transplantation to transform hepatology from a cerebral academic discipline to an activist, interventional specialty.
Successes notwithstanding, many challenges and obstacles persist. Although 1-year and 5-year survival rates exceed 85% and 70%, respectively (http://optn.transplant.hrsa.gov), the specter of hepatic and nonhepatic complications, adverse effects of immunosuppressive drugs, and potential recurrent primary hepatic disease (e.g., hepatitis C) dampens enthusiasm. In addition, liver transplantation is resource-intensive and expensive, although its costs are similar to those of recurrent hospitalizations for decompensated cirrhosis1 and its cost-effectiveness is similar to that of many accepted routine medical therapies.
Perhaps the most challenging problem is the inadequate supply of donor organs. In 2010, a total of 6291 patients underwent liver transplantation in the United States, but 11,352 new patients were added to the waiting list (see graph). The shortage of donor organs has been changed barely at all by the small proportion receiving living-donor or splitliver organs or by relaxed restrictions on — and efforts to improve viability of — donor livers that were once considered marginal. Addressing the shortage through the use of cross-species xenotransplantation, artificial livers, or stem-cell technology remains a distant, fanciful aspiration.
The selection of Starzl and Calne for the Lasker–DeBakey Award recognizes the many contributors over more than half a century who made liver transplantation what it is today.1,2,4 Credit also belongs to the courageous patients who took a leap of faith and to the funding agencies that supported the basic and clinical science that was fundamental to liver transplantation. Ultimately, the Lasker–DeBakey Award celebrates Starzl’s and Calne’s steadfastness, refusal to accept failure, and perseverance against overwhelming odds. What Starzl once said of Calne, that he had “creativity, courage in the face of terrible adversity, and vision,” applies equally to both. That thousands of patients owe their lives to these courageous pioneers is their even bigger reward.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Gastrointestinal Unit, Department of Medicine ( J.L.D.), and the Transplantation Unit, Department of Surgery (A.B.C.), Massachusetts General Hospital and Harvard Medical School, Boston.
This article was published on September 19, 2012, at NEJM.org.
1. Starzl TE, Iwatsuki S, Van Thiel DH, et al. Evolution of liver transplantation. Hepatology 1982;2:614-36.
2. Starzl TE, Fung JJ. Themes of liver transplantation. Hepatology 2010;51:1869-84.
3. Beecher HK. Ethical problems created by the hopelessly unconscious patient. N Engl JMed 1968;278:1425-30.
4. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979;2:1033-6.
5. Starzl TE, Demetris AJ, Van Thiel D. Liver transplantation. N Engl J Med 1989;321:1014-22, 1092-9.
DOI: 10.1056/NEJMp1210159
Copyright © 2012 Massachusetts Medical Society.
