**History and Evolution of Liver Transplantation**

Ayman Azzam *Alexandria University* 

*Egypt* 

### **1. Introduction**

Historically, in ancient civilization, man had already imagined changes in the morphology, structure and function of the human body. Egyptian and Greco-Roman mythology provided examples of the metamorphoses sung by Homer and Ovid, symbolic incarnations of the "comedie humaine" with its strength, weakness, vices and virtues. The liver has been the noble organ, the organ of life from time immemorial-liver in English, Leber in German, derived from the verb to live. An Indian legend from the 12th century B.C recounts the power of Shiva, who xenotransplanted an elephant head onto a child induce the Indian god Gaesha.[1] In ancient China, Yue-Jen (407-310 B.B.) induced anesthesia lasting 3 days by "the absorption of extremely strong wine, opened up the chest of two soldiers and after examining them, exchanged their hearts and transplanted them". The first reference to the concept of organ transplantation and replacement for therapeutic purposes appears to be Hua-To (136 to 208 A.D.) who replaced diseased organs with healthy ones in patients under anesthesia induced with a mixture of Indian hemp.

Although attempts at transplantation date back to ancient times, the impetus for modern transplantation was World War II and Battle of Britain. Royal Air Force pilots often were severely burned when their planes crashed. The mortality rate associated with burns corresponds to the size of the area of the skin that has been injured and the survival rate can be improved if the burned skin is replaced. For this reason, British doctors, attempted skin transplantation from other human donors as a mode of therapy. However, these attempts were uniformly unsuccessful. The transplanted skin became necrotic and fell off over several days.[2] This problem led investigators in 1940s to study skin transplantation in animal models. It remained for Sir Peter Medawar in 1944 to establish that the failure of a skin graft to "take" was the result of a process later termed immunological rejection.[3] Later studies by Gowens in 1948 revealed that lymphocytes play a major role in transplant rejection.[4] In 1951, it was shown that cortisone therapy significantly prolonged survival of skin allograft.[5] In 1959, Schwartz and Dameshek reported drug-induced immune-tolerance using 6-mercaptopurine.[6] Later in 1961, Calne and Murray showed that azathioprine therapy suppressed the rejection reaction and prolonged allograft survival.[7]

Once clinicians were confident that adequate immunosuppression was available, solid organ transplantation for end stage organ disease entered its early investigative phase. This was not possible without the application of the principles of vascular anastomosis pioneered by Alexis Carrel in 1902, for which he was awarded the Nobel Prize for Medicine in 1912.[8] Further refinements in surgical techniques and suture materials have enabled Murray and his colleagues to perform the first successful kidney transplant in 1955.[9] This was a living donor transplant performed between identical twins. However, later attempts to perform renal transplantation when the donor and recipient were not genetically identical failed because no effective immunosuppressive therapy was available. From the early 1960s, a combination of azathioprine and corticosteroids was used with success to prevent graft rejection after kidney transplantation. In 1963, Woodraff described the immunosuppressive effect of antilymphocytic serum which destroyed the recipient active lymphocytes.[10] The success of kidney transplantation paved the way to think and perform liver transplantation for end-stage liver disease.

In 1955, Welch reported on his efforts to transplant an auxiliary liver into the right paravertebral gutter of non-immunosuppressed mongrel dogs.[11] In 1958, Francis Moore described the standard technique of canine liver orthotopic liver transplantation.[12] In 1963, Starzl attempted the first human orthotopic liver transplantation in a 3-years-old boy who suffered from biliary atresia, however, the patient died before the operation was completed.[13] Following this first unsuccessful attempt, the procedure evolved slowly and although his series remained largely unsuccessful, many of the technical principles that still guide liver transplantation were established. In 1967, Starzl and colleagues at the University of Colorado reported the first successful clinical liver transplantation.[14]

Between 1966 and 1973, Starzl and colleagues performed three chimpanzee-to-human xenotransplantation of liver as well.[15] There have been 12 cases of clinical xenotransplantation including four cases of champazee-to-human, seven cases of baboon-tohuman and one case of pig-to-human.[16]

In 1978, Roy Calne opened liver transplantation unit in Cambridge, UK, and performed the first liver transplantation in Europe and the second largest transplantation series in the world.[17] Until 1977, Starzl and Calne contributed the majority of performed liver transplantation worldwide.[18]

The first hetero-topic liver transplants in man were reported by Apsolon in 1965; however, the first long-term survivor with this technique was reported by Fortner in 1973.[19]

In 1984, Shaw et al introduced the venovenous bypass system at Pittsburg University, leading to better hemodynamic stability during the standard liver transplantation.[20]

At the same time, Broelsch et al.[21] in the USA and Bismuth et al.[22] in France performed independently the first reduced-size liver transplantation. Thereafter, Pichlmayr et al.[23] reported the first split liver transplantation 1988. Meanwhile, Tzakis et al. introduced the piggyback technique with preservation of the recipient's vena cava.[24] With the increasing number of the patients on the waiting list, transplantation of partial liver grafts from living donors evoluted to increase the donor pool. For this purpose, Broelsch et al. established the technique of segmental living donor liver transplantation (LDLT), and Strong et al. performed the first successful LDLT in 1989, implanting a left lateral segment into a pediatric patient.[25] In 1990, Broelsch et al. reported the first series of LDLT in the USA.[21] In 1991, the first domino liver transplantation using liver from donors affected by familial amyloidotic polyneuropathy type I was introduced by Holmgren at al.[26] In 1992, Belghiti and coworkers introduced a modified piggyback technique with a cavo-caval side-to-side

Further refinements in surgical techniques and suture materials have enabled Murray and his colleagues to perform the first successful kidney transplant in 1955.[9] This was a living donor transplant performed between identical twins. However, later attempts to perform renal transplantation when the donor and recipient were not genetically identical failed because no effective immunosuppressive therapy was available. From the early 1960s, a combination of azathioprine and corticosteroids was used with success to prevent graft rejection after kidney transplantation. In 1963, Woodraff described the immunosuppressive effect of antilymphocytic serum which destroyed the recipient active lymphocytes.[10] The success of kidney transplantation paved the way to think and perform liver transplantation

In 1955, Welch reported on his efforts to transplant an auxiliary liver into the right paravertebral gutter of non-immunosuppressed mongrel dogs.[11] In 1958, Francis Moore described the standard technique of canine liver orthotopic liver transplantation.[12] In 1963, Starzl attempted the first human orthotopic liver transplantation in a 3-years-old boy who suffered from biliary atresia, however, the patient died before the operation was completed.[13] Following this first unsuccessful attempt, the procedure evolved slowly and although his series remained largely unsuccessful, many of the technical principles that still guide liver transplantation were established. In 1967, Starzl and colleagues at the University

Between 1966 and 1973, Starzl and colleagues performed three chimpanzee-to-human xenotransplantation of liver as well.[15] There have been 12 cases of clinical xenotransplantation including four cases of champazee-to-human, seven cases of baboon-to-

In 1978, Roy Calne opened liver transplantation unit in Cambridge, UK, and performed the first liver transplantation in Europe and the second largest transplantation series in the world.[17] Until 1977, Starzl and Calne contributed the majority of performed liver

The first hetero-topic liver transplants in man were reported by Apsolon in 1965; however,

In 1984, Shaw et al introduced the venovenous bypass system at Pittsburg University, leading to better hemodynamic stability during the standard liver transplantation.[20]

At the same time, Broelsch et al.[21] in the USA and Bismuth et al.[22] in France performed independently the first reduced-size liver transplantation. Thereafter, Pichlmayr et al.[23] reported the first split liver transplantation 1988. Meanwhile, Tzakis et al. introduced the piggyback technique with preservation of the recipient's vena cava.[24] With the increasing number of the patients on the waiting list, transplantation of partial liver grafts from living donors evoluted to increase the donor pool. For this purpose, Broelsch et al. established the technique of segmental living donor liver transplantation (LDLT), and Strong et al. performed the first successful LDLT in 1989, implanting a left lateral segment into a pediatric patient.[25] In 1990, Broelsch et al. reported the first series of LDLT in the USA.[21] In 1991, the first domino liver transplantation using liver from donors affected by familial amyloidotic polyneuropathy type I was introduced by Holmgren at al.[26] In 1992, Belghiti and coworkers introduced a modified piggyback technique with a cavo-caval side-to-side

the first long-term survivor with this technique was reported by Fortner in 1973.[19]

of Colorado reported the first successful clinical liver transplantation.[14]

for end-stage liver disease.

human and one case of pig-to-human.[16]

transplantation worldwide.[18]

anastomosis.[27] One year later, Hashikura and colleagues transplanted a left hepatic lobe into an adult recipient in 1993,[28] and Yamaoka et al. implanted a right lobe into a pediatric recipient.[29] In 1996, Lo et al. performed the first successful liver transplantation using an extended right lobe from a living donor for an adult recipient.[30] In 1998, Tzakis et al. introduced liver transplantation with cavo-portal hemitransposition in the presence of diffuse portal vein thrombosis.[31] In 2002, Cherqui et al. reported first donor hepatectomy by a full laparoscopic procedure in which a left lateral lobectomy was successfully performed for liver transplantation in a child.[32]
