The Transplanted Organs
Although Dr. Starzl played a seminal role in establishing kidney transplantation, liver transplantation was his unique accomplishment and was the main subject of 461 of his nearly 1700 peer-reviewed publications [ref 4]. By separately addressing the multiple obstacles to liver replacement in more than 150 dog experiments between 1958-61 (See: The Dog Liver Models), he elucidated principles of organ preservation, transplant pathophysiology, and surgical technology that were generalizable to all other kinds of allografts. The only learning curve that remained when he obtained a supply of azathioprine in 1962 was how to efficiently apply the drugs. This was accomplished in less than 4 months with round-the-clock canine liver and kidney experiments. After the consequent resurrection of the fading hopes of human renal transplantation (See: Kidney Transplantation), liver transplantation (Figure 1) was swept up by the momentum of the kidney successes.
Between March 1 and October 4, 1963, Starzl attempted 5 human liver replacements. The first patient bled to death during the operation. The other 4 died after 6.5 to 23 days with functioning grafts that had little evidence at autopsy of rejection or preservation injury [ref 1]. Instead, death had been caused by multiple site infections. Lung infections were associated with pulmonary emboli that formed in and migrated from the veno-venous bypasses that had been an essential component of the canine liver operation (See: The Dog Liver Models). There also were failed single attempts in Boston (Francis D. Moore, September 1963) and Paris (Demirleau, January 1964). All liver transplant activity in humans now ceased worldwide until the summer of 1967. The operation had come to be perceived as too difficult to ever be tried again.
During the self-imposed liver moratorium, Starzl’s kidney transplant program flourished, with emphasis on studies of tissue (HLA) matching (See: The Science & Politics of Tissue Matching). However, most of the activity in his animal research laboratory was liver transplant-driven. The goal was to make a broad range of improvements in the operative procedure (Figure 2), organ preservation, control of blood coagulation, and above all, immunosuppression (See: Drug Immunosuppression). In addition, patterns of infection spread to and from the canine liver grafts were mapped. It also was shown that a venovenous bypass was not mandatory in dogs whose development of venous collaterals had been encouraged by previous bile duct ligation. Most importantly, there was an evolving consensus that “brain death” was a better way to define the end of cadaver donor life than the historically-rooted “cessation of heartbeat and respiration”. The time had come to restart the human liver program.
Beginning in July 1967, multiple examples of prolonged human liver recipient survival were produced under immunosuppression with azathioprine, prednisone, and ALG [ref 2]. Julie Rodriguez, the child sitting on the knee of the Swedish surgeon, Carl Groth (Figure 3), became the first human liver recipient with survival exceeding one year. The heartbreaking sacrifices made by her parents and the lifelong bond between Dr. Starzl and the family are evident in the correspondence and other memorabilia of the Archives. After her death from graft-related complications, Dietrich Grunewald, a Swedish artist living in New Mexico, created a symbolic portrait entitled “In Memoriam Julie Rodriguez, January 1, 1966 to August 26, 1968” (Figure 4). It has been in Dr. Starzl’s home or office for the last 45 years and will go to the Archives after his death for preservation in perpetuity.
By 1969, Dr. Starzl had acquired enough successful liver cases to produce “Experience in Hepatic Transplantation”as a companion text for his 1964 kidney book, “Experience in Renal Transplantation”. Forty-two years later, Professor Jan Lerut of Louvain University acknowledged the historical role of the 2 books in his 2011 magisterial lecture to the Royal Belgium Academy of Medicine (Figure 5). In a second slide, Professor Lerut acknowledged the swarm of ideas and innovations that had been disseminated worldwide by the books (Figure 6). It had been emphasized in both textbooks that improvements with any kind of organ allograft would be applicable to all other kinds. The view was prophetic. Within 2 years after the first successful liver case, human heart (Capetown), lung (Louvain), and pancreas (Minneapolis) transplantations were accomplished, all with the immunosuppression regimen of azathioprine, prednisone, and ALG.
However, the promise of liver transplantation and of the other non-renal organs was unfulfilled for the next dozen years. Half or more of Starzl’s liver recipients treated between 1967-79 died in the first post-transplant year. The same was true in 4 newly-formed European liver transplant centers. The first was founded in 1968 by Sir Roy Calne (Cambridge, Eng.), followed in the 1970s by Henri Bismuth (Paris), Rudolph Pichlmayr (Hannover), and Rudi Krom (Groningen, Holland). Much of the medical-scientific, logistic, and administrative framework of hepatic transplantation that exists today was developed by the mutually-supportive single American and 4 European centers. Most of indications for liver transplant candidacy were obvious. Less obvious indications included inheritable disorders with known biochemical explanations (for example, Wilson’s disease of the liver). In reverse order, the acid test of liver transplantation ultimately helped elucidate the mechanisms of inborn errors (e.g. hypercholesterolemia) that had been palliated by portacaval shunt (See: Hepatotrophic Physiology).
Despite its obvious potential, liver transplantation bore the label “feasible but impractical” until Starzl combined cyclosporine with dose-maneuverable prednisone in the same algorithmic strategy that he had used to exploit azathioprine 2 decades earlier (See: Drug Immunosuppression). Liver and kidney recipients were the first to benefit. Eleven of the first 12 liver recipients treated in Colorado with cyclosporine-based immunosuppression during 1979-80 survived for more than one year. In December 1980, Starzl moved from Colorado to the University of Pittsburgh where the efficacy of cyclosporine was established for transplantation of all of the other major organs.
In December 1981, the promising developments in liver transplantation were reported to C. Everett Koop, the United States Surgeon General. Koop promptly initiated a Consensus Development Conference for liver transplantation that would include input from the 4 European centers. Prior to the Conference, Dr. Starzl prepared a summary of his American experience for presentation on November 1, 1982, at the American Association for the Study of Liver Disease (AASLD) and publication in Hepatology the same month [ref 4, item 3]. An updated version was presented to the Consensus Development Conference on June 20-23, 1983. The conclusion of the consensus committee was that liver transplantation had become a “clinical service” as opposed to an experimental procedure.
The resulting world-wide stampede to develop liver transplant centers was even more dramatic than that of kidney transplantation 20 years earlier. Only 6 years later, a 17 page article equally divided between the October 12 and October 19 issues of the New England Journal of Medicine (321:1014-1022, 1989; 321:1092-1099, 1989) began with the following statement: “The conceptual appeal of liver transplantation is so great that the procedure may come to mind as a last resort for virtually every patient with lethal hepatic disease.” It already was evident that the demand for the operation would greatly exceed both an identifiable source of organs and those qualified to transplant them. In the meantime, the waiting list for liver transplant candidacy grew exponentially, the consequences of which are described more fully in the documents that Dr. Starzl refers to as the “Paper Graveyard.”
The shortage of transplant surgeons was relieved by surgical fellows who flocked to Pittsburgh for clinical training and started independent programs elsewhere. Their education was facilitated by a change in the strategy of the operation. After it had been learned in 1963 that the potentially dangerous veno-venous bypasses were not obligatory for survival, their use was abandoned for almost 20 years. As a consequence, many liver replacements were carried out in a crisis atmosphere in which speedy performance of the vascular anastomoses was paramount. In 1982-83, a pump-driven veno-venous bypass (Figure 7) was developed, tested in dogs, and applied clinically [ref 4, item 7]. Now it was possible to do liver replacement in a relatively tranquil ambiance with reduced bleeding and minimal disturbances of blood pressure and other measures of cardiovascular function.
By the mid-1990’s the resulting exponential growth of qualified surgeons had largely caught up with the national and international need. Almost every liver transplant program director in the United States and those in of most other countries could trace their paternal or grand-paternal lineage to Dr. Starzl. However, Starzl was not finished. Beginning in 1986, he set in motion preclinical studies of tacrolimus in Pittsburgh that led to its fast-track FDA approval and its substitution for cyclosporine (See: Drug Immunosuppression). The result was improved survival with liver (Figure 8) and ultimately all other kinds of commonly performed organ transplantation. In addition, tacrolimus elevated the liver-inclusive multivisceral and intestine-alone transplant procedures developed 3 decades earlier in dogs to the status of “clinical service” (See: Multivisceral & Intestine Transplantation).
The influence of the early (1963-69) publications cited in this Discussion is evident in that these reports continue to be cited almost 50 years following their first appearances in the medical literature (Figure 9). The impact of the total collection of publications related to liver transplantation is even more remarkable: As shown in Figure 10, annual citation frequency exceeded 1600, or over 4 times per day, in the 1990s. Even today, this collection is cited over 600 times per annum.
- Starzl TE, Marchioro TL, Von Kaulla KN, Hermann G, Brittain RS, Waddell WR: Homotransplantation of the liver in humans. Surg Gynecol Obstet 117:659-676, 1963.
- Starzl TE, Groth CG, Brettschneider L, Penn I, Fulginiti VA, Moon JB, Blanchard H, Martin AJ Jr, Porter KA: Orthotopic homotransplantation of the human liver. Ann Surg 168:392-415, 1968.
- Starzl TE: Experience in Hepatic Transplantation WB Saunders Company, Philadelphia, PA, 1969.
- See Liver Transplantation Appendix for complete references and rank order citations
Human liver replacement.
The inset (right) shows bile drainage through the residual recipient duct instead of directly into the patient’s intestine (as shown on the left)
Hyperbaric oxygen chamber in which continuously infused dog (or human) livers could be preserved for up to 2 days
Professor Carl Groth with 3 long-surviving liver recipients in the summer of 1967. Julie Rodriguez is on Groth’s knee.
Slide for lecture to the Belguim Academy of Medicine (Lerut J: Liver transplantation or Starzl’s legacy. A look backward, a look forward. Bulletin et Memoires de 1’ Academie royale de Medecine de Belgique 166:381-390. 2011). Left insert: Starzl’s receipt of the Presidential National Medal of Science. Right insert: Auguste Rodin’s “The Hand of God”
Pump-driven bypass to decompress the temporarily blocked venous beds during liver transplantation
Annual citation frequency of publications cited in this Discussion. These reports, published during the 1960s, continue to be cited to date.