Liver transplantation: from inception to clinical practice.

The 2012 Lasker-DeBakey Clinical Medical Research Award will be conferred on Thomas Starzl of the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania, USA and Roy Calne of the University of Cambridge in Cambridge, UK. They are recognized for pioneering the development of liver transplantation, an intervention that saves 20,000 lives world-wide each year.

Pumping new life into old ideas: Preservation and rehabilitation of the liver using ex situ machine perfusion.

Recent advances in machine perfusion technology have reinvigorated the field of liver transplantation with the possibilities of vastly improving the efficiency and safety of the life-saving procedure. With this improved preservation technology, transplant surgeons are now able to use previously untransplantable donor livers without significantly compromising patient outcomes. Early clinical studies demonstrate the ability to extend preservation times and assess a graft's potential viability using normothermic machine perfusion, in addition to restoring the energy supply in donor livers by supporting metabolism through circulation of vital nutrients and blood-based oxygen carriers. Future endeavors for surgeons and scientists should focus on improving criteria to assess viability, optimizing protocols for perfusion research, investigating mechanisms of poor graft viability, and targeting these mechanisms with novel therapies to improve graft function prior to transplantation. Long-term goals include extending preservation times on the scale of days to weeks, enabling long-distance organ sharing, and establishing regional organ perfusion centers to streamline the procurement, perfusion, and transplantation process.

Challenge to ABO blood type barrier in living donor liver transplantation.

ABO incompatible living donor liver transplantation has the potential to expand the donor pool for patients with end stage liver diseases on the expense of challenges to overcome immunological barriers across blood type. There is a profound impact of age on incidence and severity of antibody mediated rejection (AMR). Even children older than 1 year have chances of AMR; children aged 8 years or older have risks of hepatic necrosis similar to adult liver recipients. The mechanism of AMR is based on circulatory disturbances secondary to inflammation and injury of the vascular endothelium caused by an antibody-antigen-complement reaction. The strategy to overcome ABO blood type barrier is based on both pre-transplant desensitization and adequate treatment of this phenomenon. Nowadays, rituximab is the standard means of desensitization but unfortunately an insufficient aid to treat AMR. Because of low incidence (less than 5% in the rituximab era), in practice of AMR only some case reports about the treatment of clinical AMR are available in the literature. Initial experiences revealed that the proteasome inhibitor, bortezomib might be a promising treatment based on its capacity to deplete plasma cell agents. Although ABO blood type barrier has been counteracted in 95% of patients by applying "rituximab-desensitization", many issues, such as prediction of high-risk patients of infection and AMR and secure treatment strategies for evoked AMR, remain to be resolved.

Liver transplantation for alcoholic hepatitis.

While liver transplantation (LT) has become a standard therapy for life-threatening alcohol related cirrhosis, LT as a treatment for severe alcoholic hepatitis (AH) has remained a taboo owing to concerns about the limited organ supply and the risk that the AH liver recipient will return to harmful drinking. The adoption of a 6-month abstinence requirement (the so-called '6-month rule') by many centres made AH a contraindication to LT. Given the high short-term mortality of severe AH, the lack of effective medical therapies and an increasing recognition that the 6-month rule unfairly excluded otherwise favourable candidates, a seminal European pilot study of LT for AH was performed. The success of the European study, which has been corroborated in retrospective analyses from the United States, represented a paradigm shift in therapy for highly selected patients with severe AH who are not responding to medical therapy. However, prospective studies are urgently needed to resolve the controversies that still surround the criteria for selection of patients with AH for LT and the long-term outcomes of the associated alcohol use disorder.

Liver Transplant in Colombia.

Liver transplantation began in Colombia in 1979. It is one of the most active countries in this field in Latin America but has faced problems with the regulation and appropriate management of solid organ transplantations, including transplant tourism, which is a worldwide problem. There is a well-structured donation and transplant network regulated by the government in all the stages of the process. In 2017, the country was ranked fourth for the number of liver transplantations (LTs) performed in Latin America, after Brazil, Argentina, and Uruguay, with a rate of 5.6 LTs per million population. Current regulatory bodies were created to coordinate and provide transparency and equality to transplant recipients. This article describes the evolution, government commissions, assignation criteria, and current status of LT in Colombia.

Liver Transplantation Today: Where We Are Now and Where We Are Going.

Liver transplantation was made a reality through the bravery, innovation, and persistence of Dr. Thomas Starzl. His death in 2017, at the age of 90, makes us pause to consider how far the field has come since its inception by this remarkable pioneer. It also is an opportunity to evaluate the continued novel innovations which contribute to the growth and potential for liver transplantation in the future. The liver transplant community in 2017 continued to be most significantly challenged by an overwhelming disparity between the need for liver transplant and the shortage of donor organs. The many ways in which this critical shortage are being addressed are examined in this article. The continued debate about equitable and efficacious organ allocation, "the liver wars," has dominated much of the recent past, while efforts to optimize current organ availability have also been aggressively pursued. Efforts to optimize the use of marginal and expanded criteria organs have escalated in recent years and have been accompanied by rigorous scientific evaluation. The ongoing opioid epidemic, combined with the approval and availability of highly effective hepatitis C treatment options, has allowed the increased use of HCV positive organs in HCV positive and negative recipients. Machine perfusion, both cold and warm, has moved solidly into the liver transplant world potentiating optimization of marginal donors and also offering potential modulation of liver grafts (ie, gene therapy, stem cell therapy, and defatting). Finally, pharmacological and mechanical interventions in DCD procurement techniques have contributed to improved outcomes in DCD transplants. All of these are explored in this article as a tribute to innovative spirit of Dr. Starzl and his continued impact on liver transplant today.

Current Status and Future Challenges of Liver Transplantation Programs in Chile.

Liver transplantation (LT) was performed for the first time in Chile in 1969, but only since the 1990s has it been systematically performed. Our health system is strongly centralized, which is a severe limitation for the patients who need to be evaluated and subsequently listed. Although proper human and technological resources are available and our results are comparable to international outcomes (overall patient survival at 1, 5, and 10 years of 82%, 70%, and 64%, respectively), we are limited because of a severe scarcity of grafts, which translates into an availability of approximately 7 organs per million persons and a wait-list dropout rate of 40% every year. Thus, our main challenge for the next few years is to improve access to LT among the populations from the extreme regions of the country and overall to improve the availability of grafts by increasing the awareness of physicians in intensive care units and emergency departments, to develop living donor LT programs, to educate the population in order to decrease family refusal, and to reinforce the system of potential donor detection. Although hard work is mandatory for these improvements, none of these tasks seem to be unreachable in the midterm.

Liver transplantation in the Kingdom of Saudi Arabia.

The first liver transplantation (LT) in Saudi Arabia was performed in 1991; however, it was not until 1994 that the first structured LT program was launched. Until 1997, all LTs in the Kingdom of Saudi Arabia (KSA) were deceased donor liver transplantations. Programs performing LTs needed the authorization of the Saudi Center for Organ Transplantation (SCOT), which provides the essential support for organ procurement and allocation as well as regulatory support for organ transplantation in the country. Currently, there are 4 LT centers in the KSA. Three centers are in Riyadh, the capital city of KSA, and 1 is in the city of Dammam in the Eastern province. Pediatric living donor liver transplantation (LDLT) began in 1997, while the adult LDLT program started 4 years later in 2001. Currently, more than 2000 LTs have been performed by the 4 centers in the KSA. Over 50% of those were performed at King Faisal Specialist Hospital and Research Center in Riyadh. The outcomes of these transplants have been comparable with the international standards. The aim of this review is to provide an overview of LT in KSA. Liver Transplantation 23 1312-1317 2017 AASLD.

Diego and Giorgina Vergani: The two hearts of translational autoimmunity.

Since the publication of the first textbook on autoimmune diseases in 1963, the knowledge in the field has exponentially grown into numerous tracks of research, particularly at benchside. Systemic and organ-specific autoimmune diseases, as in the case of the liver, have witnessed notable advances in terms of epidemiology, genetics, effector and regulatory mechanisms, and ultimately treatment. While the available tools for communication have provided accelerating progress rates, we recognize that key opinion leaders continue to provide significant contributions to the field. The present issue is dedicated to celebrate Giorgina Mieli-Vergani and Diego Vergani as two of the finest examples of excellence in autoimmune liver diseases and the broader field of autoimmunity. Diego and Giorgina are extremely well-liked Colleagues who fully represent the translational efforts between laboratory research and clinically relevant questions in the practice of pediatric liver diseases and autoimmune hepatitis.

The three first liver transplantations in Norway, and the road leading to them.

Although renal transplantation was a therapeutic reality in Norway from 1969, organ transplantation was largely regarded as experimental surgery from its introduction in the early 1950s until the licensing of ciclosporin in 1982. After the first successful renal transplantation in 1954, 13 years elapsed before a liver and a heart were successfully transplanted, both in 1967. Inspired by the pioneers Thomas Starzl in Denver, Colorado, and Roy Yorke Calne in Cambridge, early in 1968 Snorre Aune, Gunnar Schistad and Andreas Skulberg began experimental studies on pigs at Ullevål Hospital to develop a surgical technique for liver transplantation. They collaborated with a team at Rikshospitalet led by Audun Flatmark and performed transplantations there every other week, and every other week at Ullevål. It took over one year of weekly animal experiments before the first transplanted pig survived. The first three transplantations on humans in Norway were performed at Ward 2, Ullevål Hospital in 1969, 1970 and 1972. The first patient died shortly after surgery, the second after 24 days, the third 54 days after transplantation. Snorre Aune, Gunnar Schistad and Andreas Skulberg were awarded the Michael Skielderup gold medal in 1972 for this pioneering work. The article is based on the author's own experience as an assistant surgeon and junior partner in the animal experiments and the first human liver transplantations in Norway, and a survey of relevant publications.

[50 years of hepatology - from therapeutic nihilism to targeted therapies]. / 50 Jahre Hepatologie - Vom therapeutischen Nihilismus zur gezielten Therapie.

Over the past 50 years significant progress has been made in the whole field of hepatology. Part of this is translation of basic research (biochemistry, immunology, virology, molecular biology and others) into clinical hepatology. This enabled us to understand more about the pathogenesis of liver diseases and led to the discovery of the five major hepatotropic viruses, the identification of hepatocellular autoantigens, and to the development of specific therapies for chronic hepatitis B, C and D. In addition, the molecular basis of most genetic liver diseases has been identified. Significant progress was made in the development of medical therapies for various liver diseases with different underlying etiologies. Surgery significantly contributed to the progress in the management of liver diseases; examples are laparoscopic cholecystectomy and the development of liver transplantation. A multimodal therapeutic algorithm has been established for the therapy of hepatocelluar carcinoma (HCC); with Sorafenib "targeted therapy" has entered the area of HCC. The progress made over the last 50 years not only led to an aetiological differentiation of acute and chronic liver diseases but also to specific therapies based on the identification and understanding of the underlying etiology.

[The 50th anniversary of the first liver transplantation: from myth to reality. Tributes to Thomas Starzl, 2012 Lasker Prize]. / Le cinquantenaire de la première transplantation hépatique: du mythe à la réalité. Hommages à Thomas Starzl, Prix Lasker 2012.

Chemical immunosuppression and the reversal of rejection permit to develop kidney transplantation and were incitative to start liver transplantation in 1963. However, the difficulties were many: wrong operative indications, inadequate immunosuppression, difficulty of etiologic diagnosis of jaundice, poor preservation of the graft. Cyclosporine was the key-step of the success.

[Progress of the liver transplantation programme in Hungary]. / A hazai májátültetési program fejlodése.

The history of organ transplantation in Hungary dates back to 50 years, and the first succesful liver transplantation was performed in the United States in that time as well. The number of patients with end stage liver disease increased worldwide, and over 7000 patients die in each year due to liver disease in Hungary. The most effective treatment of end-stage liver disease is liver transplantation. The indications of liver transplantation represent a wide spectrum including viral, alcoholic or other parenchymal liver cirrhosis, but cholestatic liver disease and acute fulminant cases are also present in the daily routine. In pediatric patients biliary atresia and different forms of metabolic liver disorders represent the main indication for liver transplantation. The results of liver transplantation in Hungary are optimal with over 80% long-term survival. For better survival individual drug therapy and monitoring are introduced in liver transplant candidates.

[30 years of liver transplants in Brno]. / 30 let transplantace jater v Brne

On 3 February 1983 the first successful liver transplant in Czechoslovakia took place at the 2nd Surgery Clinic in Brno. This operation was preceded by 14 years of experiments, including more than 150 orthotopic liver transplants in pigs. Josef Mynár, a patient who suffered from an extensive liver tumour -  hepatoma -  has been living ever since, i.e. for 30 years after the transplant, leading a very active life in a good health condition.

The first report of orthotopic liver transplantation in the Western world.

Until the present time, the first experimental liver transplant which led to the development of human liver transplantation is attributed to C. Stuart Welch who performed a heterotopic transplant in the canine species in 1955. In 1956, Jack Cannon is credited with the first animal orthotopic liver transplant although the species was not disclosed. This report is intended to set the historical record straight by acknowledging that Vittorio Staudacher in 1952 was the first to perform a liver transplant in a large animal model.

Historical Background of Pediatric Kidney and Liver Transplantation in Turkey.

The cornerstone events of kidney and liver transplant history in Turkey are summarized herein. In 1975, we performed the first pediatric living-related renal transplant in Turkey. We followed this in 1978 with the first deceased donor kidney transplant, using an organ supplied by Eurotransplant. In 1979 the law on harvesting, storage, grafting, and transplant of organs and tissues was enacted; the first local deceased donor kidney transplant was performed by our team in 1979. In 1988, another ground-breaking event in Turkey, the Middle East, and North Africa was successfully achieved: the first successful deceased-donor liver transplant, and in 1990, the first pediatric living-related segmental liver transplant in Turkey, the region and Europe was performed by our team. One month later, an adult-to-adult living-related liver transplant (left lobe) in the World was successfully performed. On May 16, 1992, we performed the first combined liver-kidney transplant from a living-related donor, which was the first operation of its kind in the World. Between November 1975 and January 2022, we have performed 3288 kidney (380 pediatric) at the Hacettepe University Hospitals and later on at Baskent University; since 1988, 701 (334 pediatric) liver transplants have been performed. In over 40 years of kidney and liver transplants history in Turkey, 46876 kidney (2502 pediatric patients) and 18203 liver (2612 pediatric patients) transplants have been performed nationwide. In 2001, the Ministry of Health established the National Coordination Center as an umbrella organization to promote transplant activities, especially for deceased donor organ procurement. Transplant activities are accelerating daily throughout the country, but deceased donors are still far below the desired rates.

Operational tolerance: past lessons and future prospects.

Every liver transplant (LT) center has had patients who either self-discontinue immunosuppressive (IS) therapy or are deliberately withdrawn due to a research protocol or clinical concern (ie, lymphoproliferative disorder [LPD], overwhelming infection). This is understandable because maintenance IS therapy, particularly calcineurin inhibitors (CNI), is associated with significant cost, side effects, and considerable long-term morbidity and mortality. Detrimental effects of IS therapy include increased risk of cardiovascular disease, metabolic syndrome, bone loss, opportunistic and community-acquired infections, and malignancy. In fact, LT recipients have among the highest rates of chronic kidney disease and associated mortality among all nonkidney solid organ recipients. This mortality is only ameliorated by undergoing a curative kidney transplant, usurping costs and valuable organ resources. The search for improved treatment algorithms includes trial and error CNI dose minimization, the use of alternative IS agents (antimetabolites, mammalian target of rapamycin [mTOR] inhibitors), or even complete CNI withdrawal. Yet those who are successful in achieving such operational tolerance (no immunosuppression and normal allograft function) are considered lucky. The vast majority of recipients will fail this approach, develop acute rejection or immune-mediated hepatitis, and require resumption of IS therapy. As such, withdrawal of IS following LT is not standard-of-care, leaving clinicians to currently maintain transplant patients on IS therapy for life. Nonetheless, the long-term complications of all IS therapies highlight the need for strategies to promote immunologic or operational tolerance. Clinically applicable biomarker assays signifying the potential for tolerance as well as tolerogenic IS conditioning are invariably needed if systematic, controlled rather than "hit or miss" approaches to withdrawal are considered. This review will provide an overview of the basic mechanisms of tolerance, particularly in relation to LT, data from previous IS withdrawal protocols and biomarker studies in tolerant recipients, and a discussion on the prospect of increasing the clinical feasibility and success of withdrawal.