**Liver Transplantation in the Clinic – Progress Made During the Last Three Decades**

Marco Carbone1, Giuseppe Orlando2,3, Brian Sanders4, Christopher Booth2, Tom Soker2, Quirino Lai5, Katia Clemente6, Antonio Famulari6, Jan P. Lerut5 and Francesco Pisani6,\*

### **1. Introduction**

The World Health Organization calculates that over – six hundred and fifty million people worldwide suffer of some form of liver disease, including thirty million Americans. On a worldwide base, approximately one to two million deaths are accounted to liver related diseases annually. Around the globe, China has the world's largest population of Hepatitis B patients (approx. 120 million) with five hundred thousand people dying of liver illnesses every year (CDC, 2007; WHO, 2008). In the US alone, five hundred thousand critical liver problem episodes are reported every year requiring hospitalization with great burden to the patients and a huge cost to the health care system. In the European Union and United States of America alone, over eighty one thousand and twenty six thousand people died of chronic liver disease in 2006, respectively (CDC, 2007; Eurostat, 2007). In these patients, liver transplantation is presently the only proven therapy able to extend survival for end-stage liver disease. It is also the only treatment for severe acute liver failure and to some forms of inborn errors of metabolism.

The road to successful liver grafting in humans has been long and fraught with many obstacles. Experimental attempts at liver transplantation originally took place in the 1950s and 1960s, but human liver transplantation did not become a reality until 1963 (Starzl & Demetris, 1990). Although unsuccessful, Dr. Starzl's attempt at liver transplantation was a milestone in surgery. However, it took nearly 20 years to develop a surgical procedure for orthotopic liver transplantation (OLT) that was safe to apply in humans. In 1983, the National Institutes of Health (NIH) held the Consensus Development Conference on Liver Transplantation. The most important outcome of this conference was OLT became an accepted therapeutic modality for some patients with end-stage liver disease (NIH, 1983). The ideal liver transplant candidate needed to comply with ten conditions (**Table 1**) as well

<sup>\*</sup> *1Hepatology Unit, Addenbrooke's Hospital, Cambridge, UK* 

*<sup>2</sup> Wake Forest Institute for Regenerative Medicine, Winston Salem, NC, USA* 

*<sup>3</sup> Department of General Surgery, Wake Forest Baptist Health, Winston Salem, NC, USA 4 Wake Forest University School of Medicine, Winston Salem, USA* 

*<sup>5</sup> Starzl Abdominal Transplant Unit, University Hospitals St.Luc, Université Catholique de Louvain, Brussels, Belgium* 

*<sup>6</sup>Renal Failure and Transplant Unit – L'Aquila University, L'Aquila, Italy* 

Liver Transplantation in the Clinic – Progress Made During the Last Three Decades 179

Since the first OLT was performed, the field has changed dramatically. Improvements in surgery, anaesthesia, immunosuppression, and control of infection have translated into increased access and better patient outcomes. In the pioneering days of OLT, triple-drug therapy (corticosteroids, azathioprine [AZA], and antilymphocyte globulin [ALG]) was used to prevent and treat rejection. The development of a powerful immunosuppressive agent, cyclosporine (CsA), in the late 1970s was one of the most significant events in modern transplantation. By 1984, all transplant centers in the United States used double therapy of corticosteroids and CsA as the maintenance immunosuppressive regimen. During the 1990s, tacrolimus (TAC) emerged as the mainstay maintenance immunosuppressive agent in OLT, with or without corticosteroids. More recently, mycophenolate mofetil (MMF) has replaced the use of AZA in many centers. Before the advent of CsA, 5-year survival after OLT was less than 20%. Current survival rates 1, 3, and 5 years after liver transplantation in the

Advancements in surgical techniques and technologies also account for the increased success of OLT. In particular, the standardization of biliary tract reconstruction, advances in retransplantation, and improvements in surgical technology help explain better patient outcomes. Examples of developments in technology include pump-driven veno-venous bypass that does not require recipient heparinization, rapid infusion, and autologous autotransfusion devices. Additionally, improved procurement and preservation techniques for the donor liver and increased insight into the management of potentially fatal complications

Nowadays, liver transplantation is indicated for acute or chronic liver failure of any cause

Cirrhosis due to chronic hepatitis C infection is one of the most common indications for liver transplantation in the United States and Europe. Despite effective antiviral treatments including Pegylated Interferon, Ribavirin, and direct-acting antiviral agents (DAAs), this indication is likely to remain important for the coming decades given the large prevalence of chronic hepatitis C infection and the propensity of the disease to lead to cirrhosis and

Chronic hepatitis B has become a less common indication, mostly due to the advent of universal vaccination. Additionally, dramatic improvements in the treatment of hepatitis B, such as the development of nucleoside/nucleotide analogues, has reduced the number of patients with chronic hepatitis B progressing to end-stage liver disease. However, in parts of the world where chronic hepatitis B is endemic, including much of Asia, this remains the

Alcohol-related liver disease is an important indication for OLT in Western countries and is oftentimes associated with concomitant hepatitis C infection. In the past, patients with alcohol-related liver disease and alcohol dependence were often refused access to liver transplantation due to unjust societal allocation of scarce donor organs. However, a careful assessment with the support of a health care professional experienced in the management of patients with addictive behavior is associated with low rates of recidivism after OLT (Lucey,

United States are 88%, 80%, and 75%, respectively (UNOS, 2010).

have led to improved patient morbidity and mortality.

**2. Evolution of liver transplant indications** 

hepatocellular carcinoma (HCC) (Merion, 2010).

most common indication (Perrillo, 2009).

(**Table 3**).

as ten absolute contraindications and five relative contraindications (**Table 2**). Taking into account the multitude of criteria for OLT, few patients were deemed eligible. Furthermore, the University of Pittsburgh was the only liver transplant center in the United States in 1983. Currently, 120 liver transplant centers in the United States are registered with the United Network for Organ Sharing (UNOS), the organization that manages the nation's organ transplant system, and 145 transplant centers from 24 European countries are participating in the European Liver Transplant Registry (ELTR). As reported in the UNOS database, 111,824 liver transplantations have been performed in the United States through December 2010 (UNOS, 2010). Likewise, 100,542 liver transplantations have been performed in Europe with an average of 5,562 transplantations per year in the past decade (ELTR, 2010).


Table 1. The ten conditions to be an ideal liver transplant candidate at the 1984 NIH Consensus Conference


Table 2. The ten absolute and five relative contraindications to liver transplantation at the 1984 NIH Consensus Conference

as ten absolute contraindications and five relative contraindications (**Table 2**). Taking into account the multitude of criteria for OLT, few patients were deemed eligible. Furthermore, the University of Pittsburgh was the only liver transplant center in the United States in 1983. Currently, 120 liver transplant centers in the United States are registered with the United Network for Organ Sharing (UNOS), the organization that manages the nation's organ transplant system, and 145 transplant centers from 24 European countries are participating in the European Liver Transplant Registry (ELTR). As reported in the UNOS database, 111,824 liver transplantations have been performed in the United States through December 2010 (UNOS, 2010). Likewise, 100,542 liver transplantations have been performed in Europe

with an average of 5,562 transplantations per year in the past decade (ELTR, 2010).

Table 1. The ten conditions to be an ideal liver transplant candidate at the 1984 NIH

Inability to accept the procedure or understand its nature and/or its costs

Table 2. The ten absolute and five relative contraindications to liver transplantation at the

Advanced alcoholic liver disease in the abstinent alcoholic

Prior abdominal surgery especially in the right upper quadrant

Consensus Conference

Portal vein thrombosis

Metastatic HB malignancy

HBsAg and HBeAg positive state

Intrahepatic or biliary sepsis

Portal hypertension surgery

1984 NIH Consensus Conference

Active alcoholism

Age > 55 years

Age > 50 years HBsAg positive state

Severe hypoxemia due to right to left shunts (HPS) Sepsis outside the hepatobiliary (HB) system Primary malignant disease outside the HB system

Advanced cardiopulmonary or renal disease

**ABSOLUTE** 

**RELATIVE** 

Young patient < 50 years No viral infection No alcohol or drug abuse Normal vessel state No infection No (advanced) malignancy No cardiopulmonary or renal disease No prior abdominal surgery Ability to accept the procedure or understand its nature Ability to accept costs of the procedure

Since the first OLT was performed, the field has changed dramatically. Improvements in surgery, anaesthesia, immunosuppression, and control of infection have translated into increased access and better patient outcomes. In the pioneering days of OLT, triple-drug therapy (corticosteroids, azathioprine [AZA], and antilymphocyte globulin [ALG]) was used to prevent and treat rejection. The development of a powerful immunosuppressive agent, cyclosporine (CsA), in the late 1970s was one of the most significant events in modern transplantation. By 1984, all transplant centers in the United States used double therapy of corticosteroids and CsA as the maintenance immunosuppressive regimen. During the 1990s, tacrolimus (TAC) emerged as the mainstay maintenance immunosuppressive agent in OLT, with or without corticosteroids. More recently, mycophenolate mofetil (MMF) has replaced the use of AZA in many centers. Before the advent of CsA, 5-year survival after OLT was less than 20%. Current survival rates 1, 3, and 5 years after liver transplantation in the United States are 88%, 80%, and 75%, respectively (UNOS, 2010).

Advancements in surgical techniques and technologies also account for the increased success of OLT. In particular, the standardization of biliary tract reconstruction, advances in retransplantation, and improvements in surgical technology help explain better patient outcomes. Examples of developments in technology include pump-driven veno-venous bypass that does not require recipient heparinization, rapid infusion, and autologous autotransfusion devices. Additionally, improved procurement and preservation techniques for the donor liver and increased insight into the management of potentially fatal complications have led to improved patient morbidity and mortality.
