Lesson learnt from 60 years of liver transplantation: Advancements, challenges, and future directions

Abstract

Over the past six decades, liver transplantation (LT) has evolved from an experimental procedure into a standardized and life-saving intervention, reshaping the landscape of organ transplantation. Driven by pioneering breakthroughs, technological advancements, and a deepened understanding of immunology, LT has seen remarkable progress. Some of the most notable breakthroughs in the field include advances in immunosuppression, a revised model for end-stage liver disease, and artificial intelligence (AI)-integrated imaging modalities serving diagnostic and therapeutic roles in LT, paired with ever-evolving technological advances. Additionally, the refinement of transplantation procedures, resulting in the introduction of alternative transplantation methods, such as living donor LT, split LT, and the use of marginal grafts, has addressed the challenge of organ shortage. Moreover, precision medicine, guiding personalized immunosuppressive strategies, has significantly improved patient and graft survival rates while addressing emergent issues, such as short-term complications and early allograft dysfunction, leading to a more refined strategy and enhanced post-operative recovery. Looking ahead, ongoing research explores regenerative medicine, diagnostic tools, and AI to optimize organ allocation and post-transplantation car. In summary, the past six decades have marked a transformative journey in LT with a commitment to advancing science, medicine, and patient-centered care, offering hope and extending life to individuals worldwide.

Key Words: Liver transplantation; Model for end-stage liver disease; Liver grafts allocation; Immunology and organ rejection; Types of liver transplantation techniques

Core Tip: Over the past 60 years, liver transplantation (LT) has become an effective and well-established curative intervention for patients presenting with acute and chronic liver failure. However, the cost, complexity, and shortage of donor organs for LT has greatly challenged this intervention. Nonetheless, modifications in patient selection criteria resulting in less stringent parameters for LT patient selection, the introduction of neoadjuvant therapies, and the rehabilitation of previously unsalvageable donors have had a significant impact in countering this challenge.

INTRODUCTION

Overview of liver transplantation

Liver transplantation (LT) has proved to be an invaluable procedure, especially for patients diagnosed with hepatocellular and biliary malignancies and acute liver onditions characterized by life-threatening liver dysfunction, cirrhosis, and decompensated hepatic disorders[1]. According to Asrani et al[2], liver disorders are associated with an annual fatality rate of over two million persons globally. Therefore, liver disease and related failure accounts for one in every twenty-five deaths, with a male-to-female ratio of 3:1 across the globe[2]. This evidence places liver-related disorders as the eleventh leading cause of death globally.

Griffin et al[3], however, stressed that these liver-related deaths are grossly underestimated. Liver carcinomas and their associated malignancies account for the most significant proportion of liver-associated fatalities, with approximately 600000-900000 deaths. Based on the significant global burden associated with liver diseases and related comorbidities, LT has been associated with restoring normal body health, improving lifestyle, and extending a patient’s lifespan by at least 15 years[4]. In 2021, global statistics accounted for 34694 liver transplants globally, whereas in 2022, reported 37436 liver transplants, which accounted for an approximately 8% increase[5,6].

Transplant oncology and organ allocation

Following the introduction of LT in 1963, this intervention has been heralded as the only solid organ transplantation protocol for the curative treatment of malignancies[7,8]. In the early stages of LT, malignancy recurrence in over 60% of the cases was associated with a diminished interest in investigating oncogenic indications[9]. Nonetheless, Starzl et al[10] and the Denver group cited the impact of tumor stage and type as useful risk factors for patient selection, from which favorable prognostic outcomes could be derived. Based on this hypothesis, investigations by Yamamoto et al[11] and Iwatsuki et al[8] comparing outcomes from hepatic resections and LT outcomes in hepatocellular carcinoma (HCC) showed that early- and intermediate-stage malignancies showed a more favorable prognosis, compared with advanced-stage HCC. Similar observations were reported on oncologic outcomes based on tumor characteristics by Muhlbacher[12].

Transplant oncology, a multidisciplinary field, has garnered increased recognition and renewed attention with the term coined in 2015 and the first international consensus meeting held in 2019[13-15]. As previously established, the LT field has been shrouded by significant organ supply and demand discrepancies. The “Milan Criteria (MC)” was proposed by Mazzaferro et al[16]. In 1996, a guideline on LT patient selection was offered based on the number and size of tumor lesions, and this has been the gold-standard selection criteria for patients with HCCs, with the MC incorporated into[17,18]. Despite LT patient allocation using the MC criteria being associated with significantly favorable outcomes, several critics have highlighted shortcomings related to the criteria, including its restrictiveness[19,20].

Over the past 60 years, a more broad-based, comprehensive, and thorough understanding of the usefulness of tumor biology has led to the development of more inclusive patient selection criteria, showing a change to more dynamic criteria and allowing further assessment of tumor characteristics over time[21,22]. Several oncologic indications in LT patients exist in the context of transplant oncology. These indications include HCCs, cholangiocarcinomas (perihilar and intrahepatic cholangiocarcinomas), hepatoblastomas, hepatic epithelioid hemangioendotheliomas, metastatic neuroendocrine tumors, and colorectal liver metastases.

In the case of HCCs, several diagnostic classifications depend on geographical location, including the Barcelona Clinic Liver Cancer algorithms and Hong Kong Liver Cancer classification[23,24]. LT offers complete local tumor management in cirrhotic patients presenting with HCC. While the MC are widely used for patient selection with HCC, the University of California-San Francisco criteria (2001)[25], the Up-to-7 criteria (2009)[26], Metroticket 2.0 criteria present significant evolutions in LT patient selection with HCC. The recent New York-California (NYCA) score, incorporating absolute alpha-fetoprotein levels over time, provides a dynamic assessment of tumor characteristics[22].

Liver graft allocation

Generally, the primary objectives of LT include prolonging survival rates and improving the overall quality of life of both donors and recipients. Liver grafts are a limited and invaluable resource, with several approaches to counter scarcity adopted in clinical settings[27]. Most of these approaches are centered on increasing donor rates, alternative treatment alternatives, and reducing the overall demand for liver grafts[27]. Several common ethical directives govern the allocation process, serving the role of ethical balance in terms of justice, utility equity, and fairness in this complex process[27]. Several LT allocation policies have been developed to facilitate the best possible outcomes for LT patients on the donor waiting list, despite the limited resources at hand[27].

In the early days of center-based liver allocation, priority was typically assigned to prospective transplant candidates based on surrogate indicators of clinical urgency, such as the need for admission to the intensive care unit[28]. With advancements in outcomes and the establishment of LT as a recognized life-saving intervention, opaque and arbitrary decision-making and the wide geographical variations inherent in a center-based approach to organ allocation became unacceptable, ushering in the patient-focused organ allocation system era.

In the United States, waiting list priority was determined by the duration of waiting list time and clinical status before 1997[29]. However, evidence on this assertion concluded that the duration of transplant waiting list time did not correlate with waitlist mortality[27]. Thus, in establishing evidence-based systems, the criteria shifted from the duration of waiting list time to the prioritization of patients based on disease severity with the Child-Turcotte-Pugh classification system, the first attempt to objectify liver graft allocation[30]. The Child-Turcotte-Pugh tool criteria were primarily based on clinically assessed variables and laboratory-confirmed disease panels, such as ascites, encephalopathy, serum bilirubin levels, albumin levels, and prothrombin time[30]. The tool was also incorporated into the medical urgency-based organ allocation criteria in 1997, considering the patient’s duration on the waiting list[31].

The United States Department of Health and Human Services 1998 publication, “Final rule,” formalized the prioritization of medical urgency in organ allocation procedures over waiting time[32]. This organ allocation guidelines were devised to address several shortcomings of the objective Child-Turcotte-Pugh tool for organ allocation. These limitations were based on the tool’s subjective clinical variables, such as ascites and encephalopathy, and its failure to consider renal function as a prognostic variable, necessitating a more accurate allocation score[33].

MODEL FOR END-STAGE LIVER DISEASE

In 2002, the model for end-stage liver disease (MELD), a score based on laboratory bilirubin, creatinine, and international normalized ratio (INR) measures, was validated in the United States for recipient ranking[31,34]. This score was initially developed as an objective 3-month measure of survival prognosis in patients undergoing transjugular intrahepatic portosystemic venous shunts[35]. As a testament to its precision, the MELD score accurately predicted 3-month mortality rates for many LT patients and was deemed superior to the Child-Turcotte-Pugh score[36-38]. Following this success, the MELD score was implemented in almost all countries participating in LT procedures. Consequently, this step significantly reduces organ waitlist mortality by prioritizing the sickest patients[39].

However, a few limitations were also brought to light following the implementation of the score, including an increase in the early post-transplant mortality rate and its failure to account for elevations in INR and creatine for other non-liver-associated complications[40-42]. Moreover, the MELD score has been associated with bias against women, attributed mainly to differences in height and the failure to reflect on the potential benefits of LT in patients diagnosed with hepatocellular malignancies[43,44]. Several modifications to the MELD score have been proposed to counter these challenges, such as the pediatric end-stage liver disease[45,46].

Owing to the valuable data presented, advances in the transplant oncology field of LT patient selection have been associated with a gradual move from a static, image-based approach to a more dynamic modality, as articulated in a review by Krendl et al[47]. Notably, modifications made from the MC over the years, resulting in the NYCA score, have been hailed as a critical stepping stone. Transplant oncology posits that testing tumor biology and its response to neoadjuvant treatment represents a critical tool in LT patient selection. For instance, the study by McMillan et al[48] revealed that patients diagnosed with intrahepatic cholangiocarcinoma who underwent neoadjuvant therapy before LT presented favorable outcomes.

Similarly, several studies reporting atezolizumab and bevacizumab in patients presenting with HCCs at various stages have demonstrated significant downstaging. Subsequently, they lowered the RETREAT tumor recurrence score and were thus eligible for LT[7,49-51].

ADVANCEMENTS IN SURGICAL TECHNIQUES IN LT

Since Dr. Starzl’s first successful LT procedure back in 1963, the surgical techniques involved in the process have undergone a remarkable transition into complex, intricate, and highly efficient procedures[10]. For over half a century, research on surgical techniques and strategies for solid organ transplantation, especially LT, has unveiled several modalities involving donor and recipient surgical procedures. In Welch’s 1955 experiment, a hepatic allograft was inserted into the right paravertebral gutter of a canine specimen with considerable care to not disturb the native liver[52]. It was not until a year later that Cannon proposed the concept of liver replacement (orthotopic transplantation). These breakthroughs were closely followed by the establishment of formal research programs on total hepatectomy and LT in Canis familiaris models from 1958 to 1960[53,54].

TYPES OF LT TECHNIQUES

Conventional LT technique

The said canine experiments entailed the total removal of the native liver, excision of the retrohepatic vena cava (RVC), and replacing it with a donor liver composed of a de novo RVC segment and its corresponding connecting hepatic veins. Subsequently, anastomosis of the RVC was performed above and below the liver. This procedure is closely followed by venous and arterial anastomoses of the connecting vascular tissues (portal vein, hepatic artery, and biliary tract) using conventional surgical procedures.

These procedures have remained the general model for LT, with Starzl et al[55] adopting the same anastomosis procedure in the first human trial in 1963. This procedure remained the gold-standard surgical procedure until the 1980s, based mainly on improved survival rates, which increased to approximately 60% in the early 1980s[56,57]. According to Polak et al[58], cross-clumping of the inferior vena cava (IVC) and portal vein is associated with significant hemodynamic consequences, such as the reduction of blood backflow to the heart, congested caval and splanchnic beds, and reduced renal function. This congestion is responsible for increased bleeding during hepatectomy and can be reduced using venous bypass, which was not introduced until the mid-1980s[59,60].

Piggyback technique

An alternative surgical technique to the conventional technique is the piggyback technique, which was described by Calne and Williams[61] in 1968 and popularized by Tzakis et al[62] in the late 1980s. Contrary to the traditional approach, the piggyback method entails preservation of the IVC, allowing it to stay in situ during hepatectomy. The “classical piggyback” procedure described by Tzakis et al[62] involved using a venous outflow reconstruction between the supra-hepatic end of the donor IVC and an orifice created of the hepatic veins present. This procedure has been associated with more favorable and feasible outcomes in several studies, with the highlights being shorter surgery times, reduced blood loss, and lower costs[63-70].

Currently, the piggyback surgical technique is most widely used in LT; however, the procedure is associated with several risks, including the elevated dangers of venous outflow obstruction, with reports of hepatic venous outflow blocks evident[71,72]. Several modifications of the piggyback technique are in place clinically, such as side-to-side anastomosis proposed by Belghiti et al[73] and end-to-end anastomosis by Cherqui et al[74].

Partial LT procedures

Despite significant recent advancements in LT, the treatment modality remains one of the most complex and critically challenging procedures in the medical field. This assertion is based on the significant challenges and difficulties encountered when treating patients with different indications of hepatic failure, where recovery is not a possibility without transplantation and where liver replacement devices are used as a bridge to transplant. However, the survival rates in these cases are significantly limited[75].

Nonetheless, over the years, most established LT centers have recently documented more than 90% survival rates following 1-year post-transplantation and 80% after a 3-year follow-up[76]. Unfortunately, despite these significant strides in the field, the demand for hepatic grafts has significantly exceeded the availability of these grafts. This limited availability has been associated with more extended liver transplant waiting lists based on the shortage of viable liver donors. These developments have motivated more profound research into the field, which has unraveled worthwhile potential alternative procedures, including split grafts, living-donor LT (LDLT), and extended criteria grafts (ECGs)[75].

Split-liver technique

This procedure was first performed in 1988 by Pichlmayr et al[77] in Hannover and Bismuth et al[78] in Paris. Since 1988, split-liver techniques have been carried out widely across the medical field, with some of the most notable contributions made by Emond et al[79] in 1989, following the splitting of nine whole livers, treating five adults and thirteen children in 10 months. The procedure was, however, characterized by biliary complications in the split grafts in 27% of the cases. In a more extensive trial by Vagefi et al[80] in 2011 involving 106 liver recipients over 7 years, the results revealed 93%, 77%, and 73% patient survival rates following 1-, 5-, and 10-years post-transplantation, with overall graft survival of 89%, 75%, and 65%, respectively, in adults. In the pediatric population, patient survival was expressed as 84%, 75%, and 69%, whereas graft survival was 77%, 63%, and 57%, respectively. Biliary and vascular complications were most evident in 29% and 11% of the population, respectively.

The split-liver technique involves the division of the donor’s liver along segmented boundaries while maintaining vascular inflow and venous and biliary outflow for each division[81]. This technique employs conventional surgical methods to split the liver along the line of the falciform ligament, thus creating extended right and left grafts[82,83]. Alternatively, this split can be performed along the line at the middle of the hepatic vein, splitting the liver into full-left and full-right segments, potentially for two adult recipients[82,83].

Split-liver grafts are prepared using two generalized methods: The in-situ technique, which involves dissection and transection of the hilar and parenchyma before perfusion, and standard organ cooling during the procurement procedure[84]. The ex-vivo method involves the same process; however, in principle, this procedure is performed after procurement in the donor or recipient operating centers[85]. Recently, a systematic review by Lau et al[81] in 2021 concluded that the split-liver procedure increased the number of available livers, hence facilitating the transplantation of one donor liver to two recipients with technical advances in in-situ procedures shortening the cold ischemia time and, arguably, increasing graft quality.

LDLT

The concept of LDLT was presented at the same time as that of the split liver by Raia et al[86] between 1988 and 1989, describing the first LDLT attempt at a living donor graft in a child in Sao Paulo, Brazil. A year later, Strong et al[87] performed the first successful LDLT using a left lateral segment graft from a female donor in her 17-year-old son diagnosed with biliary atresia. The early 1990s witnessed an influx of LDLT procedures, with Hashikura et al[88] and Lo et al[89] performing successful procedures in adults using the left and right lobes, respectively, in Japan.

According to Polak et al[58], the LDLT procedure was initially designed as a measure to address the limitations in the number of liver donors and was exclusively considered for the pediatric population owing to the significantly high mortality rate of children on the liver transplant waiting list. Overall, LDLT was described as a significant success, with evidence suggesting comparable patient and graft survival across centers. Moreover, LDLT was associated with relative safety for the donor, with a 15%-20% complication rate and low mortality rate (0.1%-0.4%)[90-95].

Based on the positive results witnessed in the pediatric population (90% survival rate)[75] and the increasing queue of adults on the transplant list, LDLT grafts for adults were adopted, with the left lobes being initially used. However, the major challenge with this directive was the scarcity of left liver lobes for adults, with patients treated through this modality presenting small-for-size complications, resulting in unsatisfactory results[91,96]. Consequently, LDLT left liver lobes are still used as surgical interventions for more miniature adults and adolescents or in dual graft specifications[97-99]. However, this was not a total loss, with several centers reporting excellent patient and graft outcomes following careful patient and graft selection processes[89].

Therefore, the right-lobe LDLT graft became the most utilized LT technique in adults, with a long-term comparison close to that of whole LT. However, the rate of biliary complications and morbidity in living donors remains considerably high, especially when compared with living donors for pediatric recipients[100-104]. In terms of surgical techniques, the techniques adopted in LDLT are similar to those employed in deceased donor LT, with contrasts witnessed in complex vascular and biliary reconstructions due to multiple vessels and ducts. Moreover, excellent venous drainage in the anterior sector of the right liver lobe and an adequate graft size are critical in the post-operative function of the donated liver in LDLT, as articulated by Marcos et al[105]. These requirements render LDLT a challenging and technically complex procedure requiring specialized surgical training. LDLT, however, is very common in Japan and South Korea, where deceased donor LT was not allowed until recently based on cultural and legal barriers[106]. Moreover, LDLT procedures have recently become more prevalent in other parts of the globe, including India, Turkey, and the United States, with studies reporting excellent post-operative results[107-109].

ECGs

ECGs present another means of increasing the pool of available organs for transplantation. This modality involves the donation of liver grafts following cardiac death and low-quality grafts that were previously discarded based on their perceived low quality[75]. Current inventions in LT, primarily through hypodermic and normothermic machine perfusion, have significantly improved graft quality to the extent that organs can be incorporated into the LT process[110-113]. However, machine perfusion of renal grafts is not a novel practice in solid organ transplantation, having been around since the 1970s[114].

Moreover, studies have associated hypothermic perfusion with preserving cellular structures and rejuvenating mitochondrial functions, while producing superior outcomes in preserving ECGs, compared with outcomes realized from standard cold storage[115-117]. According to Butler et al[118], the significant merits associated with normothermic perfusion are in maintaining physiological conditions, thereby limiting the extent of endothelial damage, with similar results reported in several studies involving normothermic graft perfusion[111,113,118-120].

Domino LT

The Domino LT (DLT) concept was first described in Stockholm in 1993 during an international workshop on LT for familial amyloidosis polyneurotherapy. Subsequently, in 1995, Furtado[121] published the first successful DLT procedure in Portugal. This treatment protocol is mainly feasible in patients presenting with primarily inherited single-gene defects restricted to the liver, such as familial amyloidosis polyneurotherapy and maple syrup urine disease, with secondary debilitating extrahepatic presentation in other major body organs, such as the lungs, kidney, brain, or heart[122]. Therefore, complete liver replacement is recommended to mitigate the progression of the disease[123]. However, this liver is not entirely discarded and can be used for transplantation in another patient presenting with liver failure, as it takes one or two decades for the disease to become symptomatic in recipients[123-125]. This observation explains why DLT is primarily performed on elderly patients.

Until the end of 2019, the Familial Amyloidotic Poly-Neurotherapy World Transplant Register had recorded over a thousand (12,88) DLT procedures in over 21 countries[126]. DLT has been associated with positive outcomes, with Furtado[127] reporting overall patient survival rates of 70% and 60% in the first and third years, respectively, following the procedure. Significantly higher percentages were reported by Yamamoto et al[128], showing survival rates of 90% and 92% in the first and fifth year, respectively, following the procedure[127,128]. In a single-centered retrospective investigation by Karadagi et al[129], the overall patients’ survival rate over 5 years was documented as 79%, similar to Ahmed et al’s findings of 83%, 76%, and 57% survival rates 3, 5, and 10 years post-treatment in 2022[130].

Significant modifications have been made to the DLT procedure compared with the early procedures, such as excluding the native IVC during organ harvesting, thus improving hemodynamic stability in already compromised patients[58]. In DLT, the procedure is only performed with the prospect that the transplanted allograft will not develop any clinical or subclinical symptoms of a genetic defect in the recipient. However, several studies have suggested that DLT allografts can transmit the primary disease post-transplantation[131-137].

IMPROVEMENTS IN ORGAN PRESERVATION

Effective organ preservation remains a critical feature of successful organ transplantation. The highlight of organ-preservation modalities was witnessed from the late 1960s to the late 1980s, with the development of several revolutionary organ-preservation solutions[138,139]. First to the scene was the Collins solution, developed in the late 1960s by Collins et al[140] for storing kidney grafts, which is the earliest described preservation method for organ transplantation. In 1980, the Euro Transplant Foundation made several modifications to the solution and labeled it the Euro-Collins solution, which was the standard preservation solution in Europe for the next 15 years[140,141].

The late 1970s saw the development of Marshall’s solution, a hyperosmolar citrate solution which was associated with practical organ preservation for approximately 10 hours after harvesting[142,143]. This solution is still mainly applied in renal grafts. The University of Wisconsin also developed a University of Wisconsin solution (UWS) with a similar phosphate buffer system with high potassium and low sodium electrolyte makeup to the Collins solution[144]. The significant contrast between the two solutions was based on the replacement of glucose with raffinose and lactobionic acid, which acted as the metabolically inactive and osmotically active components of the UWS. The main reason for the inclusion of raffinose and lactobionic acid was their high molecular weight and ability to counteract transmembrane water shifts, thus preventing cellular edema, which is associated with an extended human liver graft preservation time of more than 15 hours[145].

The 1980s also saw the development of a low-potassium histidine-tryptophan ketoglutarate (HTK) solution used for the perfusion and flushing of organs and hypodermic storage during transport[146]. HTK solution is a highly used feature in general organ transplantation based on these and several other attributes, such as its closely similar composition to extracellular fluid. Recently, a mixture of the Institut Georges Lopez-1 solution and University of Wisconsin preservation solution has been broadly adopted in the LT field, with the Celsior preservation solution being a significant addition to the field[147].

For 60 years, the go-to standard of care for graft preservation has been static cold storage during solid organ transplantations[148]. However, high-risk allografts require dynamic preservation mechanisms; therefore, three active preservation methods are available for high-risk liver allografts, including normothermic machine perfusion, sub-normothermic machine perfusion, and hypothermic machine perfusion[149,150].

Normothermic machine perfusion has been associated with a 50% reduction in graft injury and organ discard in a meta-analysis comparing this modality with normal cold storage techniques[151]. Despite its high cost, normothermic machine perfusion has also been associated with significant improvements in laboratory perfusion parameters of marginal organs and can be performed in situ or ex-situ[150,152]. Meanwhile, sub-normothermic machine perfusion has primarily been applied to ECG procedures and performed at around 20 ℃ conditions[153]. This perfusion method has been associated with the mitigation of ischemia-reperfusion injury while maintaining liver metabolism and facilitating organ function assessment before LT. Hypothermic machine perfusion remains one of the most widely researched machine perfusion modalities to date, with promising outcomes reported from its application in cardiac death liver donors, revealing similar results to those of standard organ donation following brain death[154]. An investigation evaluating the outcomes of LT by Mergental et al[120] using discarded livers recovered using normothermic machine perfusion showed the survival of five livers with no complications reported during follow-up.

ADVANCEMENTS IN IMMUNOSUPPRESSIVE THERAPIES

Generally, organ transplantation would have been impossible; nonetheless, significant breakthroughs were made in the immunology field, with the most notable strides in this area documented between the 1940s and 1950s[155]. Medawar et al[156], a highly influential researcher in the field, made significant contributions after his investigations into skin grafting during World War II. He found that autografts and allografts healed successfully, but allografts were rejected in the subsequent weeks (precisely, two weeks)[75]. Drawing on Burnet’s theory of immunological tolerance, Medawar et al[156] proposed that self- and non-self-graft recognition occurs during embryogenesis[155,156]. As explained by Song et al[157], graft rejections represent an immune-mediated disorder that can be mitigated through the sustained application of immunosuppression.

Numerous immunosuppression agents have been used in LT clinical practice for over 60 years. Furthermore, adequate immunosuppression has played a crucial role in alterations linked to graft rejection and the overall survival of LTs. Progress is noticeable in the markedly reduced mortality rates among LT patients attributable to graft rejection[158,159]. Nevertheless, as time progresses, long-term repercussions of immunosuppression have emerged as a significant concern for the morbidity of LT. In addition to susceptibility to opportunistic viral, bacterial, and fungal infections, the persistent application of immunosuppression could contribute to the development of degenerative and metabolic disorders and the onset of de novo malignancies[159].

The “secret cocktail BW22” composed of prednisone and azathioprine paired with locally synthesized anti-globulins, steroid-sparing agents, were among Denver’s first immunosuppressive regimens used in solid organ transplantation[160]. However, this blend was associated with significantly low long-term survival rates, approximately 20%, cementing the need for more effective and robust immunosuppression. A retrospective analysis of findings from this procedure revealed the loss of 80% of all grafts owing to poor organ preservation methods, technical complications, cardiorespiratory complications, and immunologic complications in patients reaching tolerogenic states more than 20 years later, from this immunosuppressive regimen[161].

In the 1980s, the steroid-azathioprine blend was replaced with calcineurin inhibitor (CNI) immunosuppression, which was subsequently replaced by the mechanistic target of rapamycin (mTOR), co-stimulation inhibitors, and monoclonal antibodies (basiliximab) in the 2000s[62,162,163]. Based on their significant specificity through their selective action mechanisms, consequently leading to dosage minimization and tolerogenic suppression, CNI cyclosporine and tacrolimus are hailed as revolutionary highlights in solid organ transplantation, especially of the liver[164]. Consequently, the application of CNI cyclosporine and tacrolimus has been associated with significant increases in both graft and patient survival, leaping from 75% to 90% and 60% to 70% after 1 and 5 years post-intervention, respectively, as detailed by Starzl and Demetris[165].

In LT immunology, the initial insight was that rejection and tolerance represent different phases of a continuous spectrum. Therefore, eliminating early acute T-cell-mediated rejection at all costs may prove counterproductive to the extended survival of the graft in the long term[166,167]. This is mainly due to interruption of the route of graft acceptance, which involves an intricate interplay between specified clonal activation, deletion, and exhaustion[164]. Moreover, the extended acceptance of organ grafts under immunosuppression indicates a state of partial tolerance. The interaction between the immune systems of the donor and recipient has demonstrated positive outcomes in this context[168].

Current data on the advances made in immunosuppression for solid organ transplantation show that more than 500 multicenter trials on CNI and mTOR inhibitors have been performed globally to offer reduced cases of allograft rejection and optimize renal function[164]. Despite this progress, especially in minimizing immunosuppressive regimens, higher drug regimens (quadruple and triple) are still being applied in clinical settings[169]. Table 1 below highlights a list of the most commonly prescribed immunosuppressive drugs.

Table 1 A list of the most commonly prescribed immunosuppressive drugs in organ transplantation, adopted from Anghel et al[170].

Immunosuppression class	Drugs/therapies	Mechanism of action
Antimetabolites	Mycophenolate mofetil	Inhibition of de novo purine synthesis in lymphocytes
Biologic agents	Polyclonal antibodies (ATGAM, Thymoglobulin)	Lysis of lymphocytes
Calcineurin inhibitors	Cyclosporine A Tacrolimus	Inhibitors of an intracellular phosphate required for interleukin-2 production in the T lymphocytes
Corticosteroids	Methylprednisolone; Prednisone	Regulators of gene expression
Non-calcineurin inhibitors	Sirolimus; Everolimus	Inhibitors of mammalian target of target of rapamycin activation in lymphocytes, resulting in cycle cell arrest

IMMUNE CHECKPOINT INHIBITORS

Immunosuppressive medications have transformed the field of clinical transplantation, enabling the prevention of immune system rejection of transplanted tissues. However, the administration of drugs like cyclosporine and tacrolimus has also introduced various side effects. Prompt recognition of drug-related neurotoxicity in transplant recipients, along with understanding its specific origins, is crucial[170]. The use of immune checkpoint inhibitors (ICIs), specifically nivolumab (a PD-1 inhibitor), pre-transplant in a patient presenting with HCC was first described by Nordness et al[171]. Unfortunately, the patient developed acute hepatic necrosis based on a profound immune reaction to the ICI and passed away. Nonetheless, contradicting results reported in a study by Tabrizian et al[172], following an analysis of nine patients, showed no severe rejection incidence or graft loss, with only one mild-acute rejection reported. Moreover, Chen et al[173], following pre-transplant treatment with toripalimab, an anti-PD-1-antibody similar to nivolumab, reported a case of acute hepatic necrosis.

Several studies have highlighted the significance of the programmed death ligand-1 and PD-1 pathways in graft acceptance[174]. However, graft rejection still remains a major concern following the peri-transplantation period of LT[174]. Based on these observations, literature has suggested shorter periods between ICI administration and LT, aimed at minimizing the risk of rejection[175]. Given the 27-day half-life of nivolumab and atezolizumab, a 3-month waiting period has been suggested[176]. However, results are still contentious and conflicting as most of these statistics are based on case reports and small case series[176]. Receptor occupancy and its effect on T-cell activity, in addition to time, have also been associated with significant impacts on graft acceptance, regardless of the ICI administered[177,178].

An investigation into post-LT use of ICIs has been associated with riskier side effects, compared with pre-transplant administration. This observation has been corroborated by studies by Cesario et al[178], in an investigation of 43 patients receiving ICIs pre-LT revealing eight severe graft rejections and four deaths. In the post-LT context, severe graft rejection was reported in 15 from a pool of 52 and 7 deaths due to liver failure[178]. Interestingly, acute graft rejection in the liver is very rare, thus, acute graft rejection post-LT in patients receiving ICIs calls for further investigation into this incidence. Montano-Loza et al[179] called for much close monitoring of patients administered ICIs in a decision table on the use of ICIs in LT recipients, based on individual risk and oncological usefulness.

Despite limited experience with ICIs, several studies have highlighted the absence of graft rejection incidence in 10 patients treated with atezolizumab, a PD-L1 antibody, regardless of the time of administration[50,51,178]. PD-L1 expression has been suggested as a potential biomarker based on its correlation with an increased risk of rejection[178].

COMMON MEDICAL AND SURGICAL COMPLICATIONS IN LT

In the early days of LT, survival rates the overall survival rate for the patients was about 30%, with most patients succumbing to rejection or infection[165]. Several studies put the overall survival rate of LT patients between 50% and 70%, depending on the type of indication[180,181]. Among these, indications with better survival outcomes in the long term are primary biliary cirrhosis and autoimmune cirrhosis. On the other hand, Hepatitis C and hepatocellular tumors have the worst outcomes, generally due to high recurrence rates[181].

Several factors are associated with overall LT survival rates, including donor and recipient characteristics, and perioperative and post-operative features[182]. Advanced age (> 50 years), high body mass index (BMI), prolonged hospitalization, use of vasopressors, and infection rates have been identified as indicators of poorer outcomes in donors. On the other hand, renal dysfunction, old age, urgent indication, poorer nutritional status, presence of infection or hepatitis, and requirement for mechanical ventilation are indications of poorer outcomes in recipients[182]. Perioperative conditions, such as cold and warm ischemia duration, requirements for blood transfusion, surgical challenges, and post-operative indications, including renal dysfunction, need for mechanical ventilation, extended intensive care unit stay, and primary dysfunction, are some of the factors associated with poor outcomes in LT[182].

Common medical complications in LT

Primary graft dysfunction: Primary non-function caused by early allograft dysfunction (EAD) represents one of the most dangerous complications of LT[183]. According to Agopian et al[184], EAD incidence is between 5% and 40% in all LT patients. The application of the model of early allograft function (MEAF) score[185] and liver graft assessment following transplantation (L-GrAFT) risk score facilitates the quantification of the levels of dysfunction[184]. The MEAF score evaluates parameters in terms of maximum alanine aminotransferase, INR, and bilirubin levels three days post-surgery, and has also been applied in the prognostic evaluation of LT patients within the first year following surgery[186]. Meanwhile, the L-GrAFT score is applied for the prognostic assessment of graft failure three-months post LT[184].

Cold and warm ischemia durations, in addition to indicative donor parameters such as elevated BMI, steatosis, and cause of death, are some of the most documented risk factors for early graft dysfunction[187]. However, a recent study has shown that an elevated serum sodium level in the donor can be linked to higher rates of EAD[188], although conflicting findings on this assertion exist in the literature[189]. Moreover, recent investigations on the duration of donor extraction, i.e., the time taken from the aortic cross-clamp to the actual liver extraction, showed a correlation between this time and EAD rates[190].

Early graft dysfunction and primary graft non-function have a significantly higher incidence [up to 3.6-fold-after donation after circulatory death (DCD) compared with donation after brain death (DBD); yet survival rates are comparable with appropriate perioperative management[191-193]. Investigations conducted by Marcon et al[194] reported higher (though not statistically significant) rates of primary non-function, hepatic artery thrombosis (HAT), and ischemic cholangiopathy in recipients of previously discarded livers. The study also underscored the persistent disagreement among specialists, importance of expertise (including in the procurement phase), and necessity for proper donor/recipient matching to curb such outcomes[194].

Graft rejection: Graft rejection in LT is described in three general stages: Hyperacute (within hours following the transplantation procedure), acute (rejection occurring within 2-6 weeks after transplantation), and chronic rejection[195]. The hyperacute phase is characterized by manifestations similar to ischemic graft injuries[189]. ABO incompatibility between donor and recipient antibodies is the primary cause of this rejection. However, the prevalence rates of this type of rejection are meager, and urgent re-transplantation is recommended[189].

Secondly, the acute phase has been described as the most clinically frequent type of graft rejection, with an overall prevalence rate between 15% and 20% in all LT patients[189]. This type of rejection is mainly attributed to the T-lymphocyte response to the liver graft with old age, tacrolimus, and cirrhosis from alcohol abuse, identified as significant risk factors for this type of organ rejection[189]. The phase is also characterized by non-specific symptoms such as fever, pain, jaundice, malaise, and altered bile production. Steroids and increased immunosuppression regimens present the first-line treatments for this rejection phase[189].

Finally, the chronic graft rejection phase is primarily characterized by ductopenia and macrophages’ total obstruction of the arterioles. This phase has been further associated with periportal edema, biliary dilatation, ascites, and hepatosplenomegaly following a year after transplantation[167,196]. Ramirez posited that this type of graft rejection is a consequence of cytomegalovirus infection, recurrent acute rejection, graft ischemia (related to artery stenosis), and antibody-mediated chronic rejection[189]. Steroids and graft retransplantation are the only feasible treatment interventions with studies showing the practical application of tacrolimus[197].

Post-transplant infections: Current organ transplantation guidelines emphasize the need for recipient screening for all acute or chronic infections (fungal, bacterial, or viral)[187]. Among the most documented infection contraindications for LT include HIV 1 and 2; hepatitis A, B, and C; CMV, tuberculosis, EBV, HHV, VZV; herpes simplex virus 1 and 2, among other venereal infections[187]. HIV 2, however, is not an absolute contraindication for liver transplant under current guidelines[187]. These guidelines stress the need for LT screens and precisely detailed reports of the local epidemiology of recipients, such as coccidioidomycosis and secondary prophylaxis screening[187]. Further details on disease-associated contraindications, vaccination regimens, and prevention protocols for LT can be found in studies carried out by Fagiuoli et al[198] in 2014.

Surgical stress and immunosuppressive therapy have been associated with higher susceptibility to infection, with most LT patients being highly likely to suffer from some infections[187]. The most common infections within the first month post-transplant are bacterial and fungal infections at the incision sites, abdomen, bloodstream, urinary, and respiratory tracts[195]. Studies have shown that a higher graft loss rate is significantly associated with intra-abdominal infections[195]. These infections, however, can be mitigated by selective bowel decontamination using nonabsorbable oral antibiotics[199]. All Clostridium difficile infection risk factors must be mitigated[195].

In the first to the sixth months after surgery, opportunistic pathogens or activated latent-caused infections, such as HHV, CMV, and toxoplasma, among others, are common with prophylaxis and preemptive therapies applied to these infections[159]. Detailed intervention and infection management protocols have been described by Lucey et al[159], Esch et al[200], Gavaldà et al[199], Martin et al[201], and Muñoz et al[202]. Community-acquired infections, including respiratory, urinary, tract, and respiratory infections, are more common after 6 months of LT, with daily lifestyle changes, such as frequent hand-washing, use of gloves, smoking cessation, and avoiding decontaminated food and water, advised for these complications[199].

Other post-operative complications: Pulmonary complications associated with long surgery time, interoperative blood loss, liquid infusion, blood transfusion, sepsis, and changes in hemodynamic status are the most frequent complications after LT[187]. Moreover, pleural infusions in the right chest area, which can cause atelectasis and pneumonia (presenting in 5%-38% of LT patients), normally are self-healing, but in case of persistence, are treated using targeted antibiotic therapy and withdrawal of immunosuppression[189,203].

Moreover, the incidence of adult respiratory distress syndrome has been reported in about 4.5%-16% in all LT patients, with a mortality rate of about 80%[204]. Pulmonary edema caused by fluid overload, primarily due to renal failure, has been reported, although rarely[203]. Post-reperfusion syndrome (PRS) caused by severe ischemic or reperfusion liver injury has been recorded in over 55% of LT patients post-reperfusion[205]. Clinically, postreperfusion manifests as lowered cardiac output and reduced vascular resistance. PRS usually is an early indication of acute kidney injury (AKI), which affects close to 78% of LT patients. Significant risk factors for AKI include old donor age, high donor MELD score, high BMI, and an elevated need for intraoperative blood transfusion[191].

LT procedures have also been associated with an occurrence of neurologic complications occurring within the first month and up to a year following treatment. These complications have been described as multifactorial, and are inclusive of seizures, focal motor deficits, and encephalopathy[206]. Encephalopathy is the most common neurological complication, with a prevalence of between 1%-3% and an etiology primary from impaired graft function, the incidence of sepsis, and the use of CNI-immunosuppressants or steroids, among other causes[207,208]. Post-LT demyelinating inflammatory polyneuropathy is another complication, although rarely occurring[209].

Other complications

Cardiovascular complications: These complications account for about 25% of the mortality in LT patients 10 years following treatment[210,211]. Some of the most common risk factors, especially in LT patients, include hypertension (a common disorder in LT patients affecting between 36% and 77% of all patients), renal damage, diabetes mellitus, obesity, CNI immunosuppression, and steroid use. To curb these complications, studies have emphasized the need for lifestyle changes and pharmacological investigations including calcium channel blockers, beta-blockers, and angiotensin-converting enzyme inhibitors[189,212].

Metabolic syndrome and kidney diseases: Metabolic syndromes, such as hypertension, dyslipidemia, obesity, and insulin-resistant diabetes mellitus are associated with the development of post-LT non-alcoholic fatty liver disease and non-alcoholic steatohepatitis[213].

According to Gonwa et al[214], 5 years after LT, about 80% of LT patients develop chronic kidney disease, with 10% of this population needing dialysis or kidney transplantation within the next 10 years. Studies investigating the association between LT and kidney disease have articulated the application of CNI, leading to the occurrence of tubulointerstitial chronic fibrosis as a significant risk factor associated with kidney diseases in LT[215]. Moreover, post-transplant CMV infection, metabolic syndrome, and pre-transplant kidney dysfunction or impairment have been listed as significant risk factors[205].

Bone and dermatological non-oncologic complications: Bone complications resulting from cholestatic disease affectapproximately 65% of LT patients[216]. The etiology of this disease has been attributed to changes in hormonal levels induced by liver malfunction, resulting in the rearrangement of bone metabolism, in addition to IS and steroid use[216]. These conditions are treated with standard bone therapies such as osteoporosis.

Dermatological non-oncological complications encompass a significantly wide range of disorders, such as xerosis cutis, sebaceous hyperplasia, and steroid-induced acne, among others[187]. These complications occur within the first month following LT but subsequently improve. However, herpetic and fungal infection, and tinea of the nails and skin are more prevalent in LT[217].

Recurrent liver infection: Some of the most recurrent liver infections after LT include viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis (PSC). This recurrence is significantly associated with the application of immunosuppression, which facilitates faster disease development[218]. This recurrence has been reported in up to half of patients undergoing LT; however, this recurrence does not significantly affect the patient’s prognosis.

De novo malignancies: These malignancies account for about 21%-25% of all functioning graft mortalities, with studies describing these malignancies in LT as highly aggressive[219,220]. De novo malignancies in LT are classified based on their causes, with the most recognized stratification being recipient factors and lifetime immunosuppressive therapies, as described by Watt et al[221]. This stratification articulates that recipient factors such as the presentation of PSC are associated with the development of non-skin cancer in about 22% of transplanted liver patients within ten years[221]. Moreover, in recipients diagnosed with HCC, 20% of these patients transplanted with livers have an increased probability of HCC recurrence between the 2^nd and 25^th years after transplantation[222]. Lifelong immunosuppression is associated with immune surveillance deficiencies that promote malignant cell survival and proliferation[187]. Moreover, immunosuppressive therapies are known to reactivate latent oncogenic viruses such as HHV.

In LT recipients, skin cancers are the most common type of malignancy, with a 20-fold higher risk, compared with other transplantation therapies[223,224]. In LT recipients, Kaposi’s sarcoma, basal cell cancer, and squamous cell cancer are the most common de novo malignancies[225]. Secondly, post-transplant lymphoproliferative disorder, with a global incidence rate between 5% and 20%, is the second most common de novo malignancy, especially in the pediatric population, within the first 18 months following surgery[225].

Sarcopenia: Sarcopenia, described as a decrease in muscle mass and strength often related to old age, presents an exceptional risk factor among LT candidates due to chronic illness, malnutrition, hypermetabolic conditions, medication and treatment side effects, and a persistent inflammatory state[226,227]. A 2016 study by van Vugt et al[228] estimated that 22%-70% of patients diagnosed with end-stage liver disease present with sarcopenia. The incidence of sarcopenia in LT is a relevantly new area. A retrospective study of 142 patients in the University of Alberta liver transplant waitlist revealed that sarcopenia was associated with a 2.4-fold independent risk factor for mortality, especially in patients with MELD scores below 15[229]. A similar study conducted in patients in the LT waitlists showed a 15% increase in mortality susceptibility in patients presenting with sarcopenia[230]. Nonetheless, these assertions have been challenged by contradictory results from two studies by Yadav et al[231] and Wang et al[232]. A retrospective analysis of 396 patients presenting with end-stage liver disease has however, reinforced the association between sarcopenia and waitlist mortality, while also elucidating the significant costs associated with the disease in LT patients[233].

In the post-LT context, sarcopenia has been strongly associated with significantly poor post-LT outcomes in LT patients post transplantation, associated with a 4.8-time higher risk of mortality after a year, compared with non-sarcopenic patients[228,234,235]. several studies have listed sarcopenia as a significant risk factor in the incidence of adverse post-transplantation-related pulmonary events[236-238]. Several interventional therapies have been proposed in the management of sarcopenia including exercise programs, branched-chain Amino acid supplements, myostatin inhibition, and testosterone supplementation[227].

Biliary complications: These are quite common complications of LT, with incidence rates ranging from 2% to 19% globally, leading to post-operative morbidity and mortality rates[101,239,240]. Biliary leakage and biliary strictures are the most common types of biliary complications in LT, whereas intrahepatic strictures, papillary dysfunction, stone-caused, and cystic duct mucoceles are less frequent[240,241]. Bile leaks, with an 8.2% incidence, occur in the first to sixth months after the LT procedure[239]. Some of the most documented leakage sources of these complications include biliary anastomosis, cystic duct stump, liver surface or section injury, and technical mistakes[189]. Bile leaks manifest clinically as fever and abdominal pain with conservative management, such as biliary decompression[239].

Extrahepatic biliary strictures (EBS) present another most common form of biliary complication that affects at least one-third of the patients, normally occurring in the first years after LT[240]. Some of the most notable risk factors associated with EBS include edema, BL, HAT, or hepatic artery stenosis (HAS), biliary infections, and twists in the anastomotic stump. Ischemic-type biliary strictures/ischemic cholangiopathy or intrahepatic biliary strictures, presenting in 3%-16% of all LT patients, are worrisome biliary complications occurring within the first 6 months[241]. Over half of these patients will require re-transplantation and are a consequence of ischemic injuries leading to the development of fibrosis[241].

Surgical complications

Post-operative hemorrhage: This complication has been seen in approximately 5% of LT recipients, normally occurring within 48 hours post-surgery. Delayed graft function, thrombocytopenia, hypercalcemia, and dilution represent some of the most documented risk factors[189].

Vascular complications: These surgical complications have been documented in about 7% of all organ transplantation procedures and are significantly associated with elevated graft loss and mortality rates, with the poorest prognosis highlighted when these complications are diagnosed late[242]. One of the most common forms of vascular complications is HAT, with a 1.9%-9% incidence rate. HAT has been described as the leading cause of graft loss in organ transplantation, with the highest incidence rates observed in pediatric recipient population compared with adult recipients (42% vs 12%, respectively)[242,243]. Some of the most common risk factors associated with HAT include the need for blood transfusion, recipient hypercoagulability, prolonged cold ischemia time, damage to the endothelium, technical mistakes, and transplantation in low-volume institutions[243].

HAS represents another prevalent vascular complication in LT, with an incidence range of 0.8%-10%[242]. Technical injury, vessel injury, or twists/kinks in the vascular vessels have been attributed to HAS incidence, with patients remaining asymptomatic, whereas over 50% may experience subsequent HAT[189].

One of the rarer vascular complications in the hepatic artery pseudoaneurysm, with a 1%-3% incidence, develops in about 2-3 weeks after LT[244]. Studies have shown that fungal infection at anastomotic sites can result in a pseudoaneurysm in the extrahepatic tract[244]. This complication can be treated through arteriography, embolization, and urgent retransplantation. A similarly possible complication is arterial conduit occlusion, which has an incidence rate of about 8% in instances where utilization of the native artery is not feasible. Older age (above 40 years) and the incidence of prior coronary artery bypass are significant risk factors.

Technical mistakes during surgery, such as twists or kinks in a redundant vessel and low flow through the vessel, are the principal causes of portal vein complications. Portal vein stenosis, with an approximately 5% incidence rate, presents the highest risk factor for split-liver, LDLT, and pediatric recipients[245]. Moreover, portal venous thrombosis, with an incidence of 2%-3% associated with a state of previous hypercoagulability and manifesting as sudden acute liver failure symptoms, portal hypertension symptoms, renal failure, and hemodynamic instability, is another known vascular complication of LT[189].

ETHICAL AND LEGAL CONSIDERATIONS IN LT

The rate of annual LT has significantly increased from the early days of LT. Despite these advances, liver grafts remain a scarce resource, with an estimated mortality rate of 15% among patients on waiting lists[246]. Several issues have emerged over the years regarding priority in terms of allocation, especially in instances where liver disorders are attributed to the patient’s own choices, such as alcoholism and lifestyle choices. Thus, the scarcity of this life-saving resource warrants the incorporation of legal and ethical frameworks of equity, justice, utility, and benefits when prioritizing organ transplant recipients. According to Mellinger[247], the major bioethical guidelines and principles governing not only LT but also all aspects of organ transplantation include autonomy, non-maleficence, justice, and beneficence.

Following controversies surrounding liver allocation and prioritization frameworks witnessed in the early days of LT, a set of guiding principles was established to govern and assist in this accord carefully. In the 1960s, in the United States, the federal government became actively involved following the coalescing of local and regional organ-sharing programs, which came under the governance of the Public Health Service[247].

The establishment of the United Network for Organ Sharing (UNOS) in 1983 saw the transfer of these responsibilities from the Public Health System to the UNOS by Weimer[248]. 1983 also saw the declaration of LT as no longer an experimental treatment by a consensus conference of the National Institutes of Health in the United States by Weimer[248]. Subsequently, in 1984, following successful legislation of the National Organ Transplant Act, the Organ Procurement and Transplant Network (OPTN) was charged with ensuring ethical and legal organ donation, allocation, and transplantation. The OPTN is a private organization contracted by the Department of Health and Human Services to ensure the management of organ donation and allocation. A detailed copy of the OPTN guidelines, standards, and governance platform can be found at https://www.hrsa.gov/optn-modernization[249].

Moreover, the Uniform Anatomical Gift Act (UAGA), passed in 1968 and revised in 1987 and 2006, presents a set of legal standards in regard to organ donation with respect to altruism, autonomy, and maintaining public trust frameworks[250]. The Organ Procurement Organization (OPO) is charged with approaching families and eligible donors for donation while still assessing the feasibility of donated organs. OPOs are independent organizations and thus are located separately form organ transplantation centers, allowing them to reduce any conflicts of interest[247]. Under the UAGA protocol, physicians declaring donor deaths are prohibited from being involved in any aspect of organ donation and require hospitals to notify the OPO in incidences of imminent or actual death for registered organ donors for suitability assessments and family approaching[251].

In the United Kingdom, the Human Tissue Act of 2004 governs the process of organ donation with the process of organ donation to allocation under the management of the National Health Services’ Blood and Transplant[247]. Organ donation frameworks are present in individual countries, which may be similar or different from the United States or United Kingdom frameworks. However, international organizations such as The European Union Directive on Organ Donation and Transplantation and the World Health Organization have set up their guidelines and legal frameworks governing organ allocation processes.

Autonomy

In organ transplantation, especially LT, the principle of autonomy, requiring respect for individual decisions and choices made on a patient’s or donor’s body and healthcare, is a critical legal and ethical requirement[247]. In the majority of countries, organ donation is viewed as “a gift”. Per the United States laws under the UAGA, the primacy if the donor should be respected, i.e., “where the deceased’s wishes were known, next of kin does not have to give consent for donation and cannot override the deceased’s stated wishes for donation”[247]. Several limits to autonomy exist, such as in instances in which the deceased patient’s mental capacity is compromised, incapacitation to the extent that the patient cannot make sound medical decisions, or in the case of children.

Beneficence and non-maleficence

This framework is largely applied in cases of extended criteria donor requiring through assessment and evaluation of the risk of transplanting higher-risk organs associated with significantly poor prognostic and operational outcomes against the risk of death while recipients are on the waiting list[247].

Deceased from circulatory death donors and deceased from brain death donors

This legal and ethical framework employs the “donor death rule”, which requires that all viable donors should be declared dead prior to any organ retrieval. Thus, the framework exempts physicians from declaring death from any process of organ donation, which consequently forms a critical tool for fostering public trust and preventing any conflicts of interest[247]. Following a consensus in 2006 defining DCD and outlining ethical and medical guidance for organ donation following DCD, the criteria have been implemented widely, raising the number of available liver grafts[252]. This criterion is based on two principles: Firstly, DCD and DBD are declared in the event of total cessation of function, and secondly, this cessation is irreversible[247].

Utility

This framework demands that the best possible outcome be maximized. In LT, especially in DCD transplantation, biliary ischemia resulting in ischemic cholangiopathy and graft loss, which requires re-transplantation, is the most common risk factor, as documented by Feng et al[253] and Jay et al[254]. Thus, the framework emphasizes maximizing utility by minimizing the rates of poor outcomes, which entails proper selection of donors and recipients, minimization of cold and hot ischemia time, avoiding donors above 50 years and with a higher body mass, and preservation of DCD and DBD organs for patients with MELD scores higher than 20[255].

FUTURE DIRECTIONS AND CHALLENGES IN LT

Regenerative medicine and cell-based therapy

The liver represents one of the major body organs tasked with maintaining the homeostasis of nutrients and energy metabolism. Additionally, the liver serves as a detoxification, deoxidation, bile-producing, and secretory protein synthesis organ. Based on the complexity and high levels of toxicity attributed to these processes, the liver is exposed to a significant number of pathogens and other toxins. Thus, the liver is at greater risk of developing diseases such as hepatitis, cirrhosis, cancer, and other forms of liver disease (acute or chronic). The 21^st century has been marked by tremendous efforts in the field of medicine, with further investigations in the field of organ transplantation, identifying cell-based and regenerative therapies as potential replacements for LTs[256].

Cell-based therapies or stem-cell-based therapies involve the stepwise modification of pluripotent stem cells into hepatocyte-like cells in in vitro settings and in the presence of growth factors[256]. The maturation of these hepatocyte cells can then be monitored based on their gene expression, functional protein presentation, secretion, and overall capacity for metabolism. This approach has been largely applied in mouse models, as expressed in investigations by Du et al[257]. Cell-based therapy has been associated with two critical roles, i.e., control of disease progression through the stimulation of endogenous regeneration and inhibition of fibrosis[258].

Over the past 15 years, hepatocytes, macrophages, and stem cells have been transplanted as a bridges to surgery, supporting liver function. Firstly, hepatocyte therapy has been the go-to cell therapy for chronic liver disease as it has been associated with the induction of modest reductions in levels of ammonia and encephalopathy in both human and animal models[259]. However, this therapy has several drawbacks, including the significant difficulty encountered in isolating an adequate quantity of high-quality and metabolically active cells. These hepatocytes are harvested from non-feasible livers with variable levels of quantities and qualities[260]. Secondly, hepatocytes are known for their rapid deterioration when cultured in vitro and their subsequent sensitivity to freeze-thaw damage; thus, they are significantly affected by culture methods, materials, and cryopreservation methods[261].

Hepatic macrophages have been identified as key players in the dual-way process, reversible dynamic fibrogenesis-fibrosis resolution paradigm[262,263]. Based on investigations by Thomas et al[264] on the role of monocyte- or macrophage-based approaches in damping liver fibrosis in animal models of chronic liver injury, the administration of bone marrow-derived macrophages has been associated with improved liver fibrosis, regeneration, and an overall therapeutic benefit.

Liver tissue bioengineering

Tissue engineering, specifically three-dimensional cultures, has been associated with several advantages over two-dimensional cell cultures[228,230]. This three-dimensional approach has been instrumental in vitro models, especially in complex liver tissues, which are associated with interactions between hepatocytes, hepatic stellate cells, and the extracellular matrix (ECM)[200].

The quest for effective biocompatible scaffolds is directed towards the creation of organic or polymeric structures that emulate the liver's ECM and reproduce functional attributes like cell adhesion, viability, growth, and proliferation. Principal strategies revolve around biomaterials, including polymer-based three-dimensional (3D) constructs, decellularized ECM, and bioprinting of 3D structures. Another recent strategy involves the implementation of bioreactors to enhance various functions of hepatocytes within these constructs. Within bioreactors, a genuine 3Dmicroenvironment is established to enhance cell attachment, growth, and proliferation. This marked improvement in liver metabolism and function is achieved through optimization of the microenvironment niche.

Artificial intelligence in LT

Artificial intelligence (AI) is playing an increasingly important role in LT, enhancing various aspects of the process from pre-transplant evaluation to post-transplant care. One of the key areas where AI is making a significant impact is in the evaluation and selection of transplant candidates. Machine learning algorithms are being developed to predict outcomes, such as graft survival, patient survival, and the likelihood of complications[265-267]. These models analyze large datasets that include patient demographics, medical histories, and liver disease severity to help clinicians identify the most suitable candidates for transplantation[268]. AI's ability to integrate and process vast amounts of data allows for more accurate risk stratification, enabling better prioritization of patients who are most in need of a transplant.

Additionally, AI has the potential to refine existing scoring systems like the MELD score by incorporating a wider range of variables, thereby improving the accuracy of predictions related to patient outcomes. AI is also being utilized to optimize organ matching and allocation processes[269,270]. Traditional methods for matching donors to recipients are being enhanced by AI algorithms that can analyze a more comprehensive set of factors, including genetic markers, liver anatomy, and immune profiles. This leads to better compatibility between donors and recipients, potentially improving graft survival and reducing the risk of rejection. Furthermore, AI can optimize the overall organ allocation process by taking into account medical urgency, geographical proximity, transportation logistics, and cold ischemia time. This holistic approach ensures that organs are allocated in a manner that maximizes patient outcomes, while also addressing logistical challenges[269,271].

During the surgical phase of LT, AI provides valuable support for both planning and execution. AI-powered image analysis tools assist surgeons by generating detailed 3D reconstructions of the liver and surrounding vasculature, which are particularly beneficial in complex cases involving anatomical variations or tumors. These advanced imaging techniques allow for more precise surgical planning and reducing the risk of complications during the operation. Moreover, AI systems are increasingly being integrated into robotic surgery platforms, offering real-time guidance by identifying anatomical structures and predicting potential bleeding points. This intraoperative support enhances a surgeon’s ability to perform delicate procedures with greater accuracy, ultimately improving the overall success of the transplantation.

Post-transplantation AI continues to play a crucial role in monitoring patient health and managing potential complications. Predictive models are being developed to anticipate issues, such as graft rejection or infection, enabling earlier intervention and improving long-term outcomes. By continuously analyzing patient data, AI systems can identify subtle changes in biomarkers or clinical indicators that may suggest a developing problem, allowing for more proactive and personalized care. As AI technology continues to evolve, its integration into LT is likely to become even more sophisticated, offering the potential for further improvements in patient outcomes, resource allocation, and overall efficiency of the transplant process.

CONCLUSION

Over the past six decades, LT has evolved from a groundbreaking surgical intervention into a standardized and life-saving procedure that has transformed the landscape of organ transplantation. The journey has been marked by a series of remarkable milestones, innovations, and paradigm shifts that have substantially improved patient outcomes and expanded the understanding of LT as a complex and dynamic field.

The initial breakthroughs in the 1960s and 1970s, culminating in the first successful human LT performed by Starzl et al[10] in 1967, set the stage for a new era in medical science. Subsequent decades witnessed advancements in surgical techniques, immunosuppressive therapies, and organ preservation methods, which have contributed to increased success rates and expanded access to LT. The introduction of cyclosporine in the 1980s revolutionized immunosuppression, significantly reducing the risk of graft rejection, and improving overall graft survival.

The late 20^th century saw the refinement of organ allocation systems, addressing ethical concerns and ensuring a fair distribution of available organs. The MELD scoring system, implemented in the early 2000s, represents a landmark shift towards a more objective and transparent approach to organ prioritization based on the severity of illness. This contributed to a more equitable allocation of organs and optimized outcomes for patients awaiting transplantation.

Technological advancements have played a pivotal role in enhancing the field of LT. Imaging modalities such as computed tomography and magnetic resonance imaging have improved preoperative assessment and surgical planning. Additionally, the advent of machine perfusion techniques, both normothermic and hypothermic, has allowed better preservation and assessment of donor organs, expansion of the pool of viable grafts, and minimization of ischemia-reperfusion injury.

The past two decades have witnessed a surge in LDLT, offering a unique solution for the growing demand for donor organs. Advances in surgical techniques, donor safety, and post-operative care have made LDLT a viable option for selected patients. Simultaneously, split LT and utilization of marginal grafts have further broadened the donor pool, addressing the persistent challenge of organ shortage.

Immunological research has deepened our understanding of graft-host interactions, paving the way for personalized and targeted immunosuppressive strategies. The emergence of precision medicine in LT involves tailoring treatments based on individual patient characteristics, genetics, and immune responses, leading to improved graft survival and minimal adverse effects.

Clinical outcomes have witnessed significant improvements over the years, with overall patient and graft survival rates reaching commendable levels. Short-term complications, such as EAD, have been scrutinized, and strategies to mitigate these challenges have been implemented, resulting in enhanced post-operative recovery and long-term outcomes.

Looking forward, ongoing research endeavors focus on refining diagnostic tools, exploring regenerative medicine approaches, and leveraging AI to optimize organ allocation and post-transplant care. Continuous collaboration between clinicians, researchers, and policymakers will be pivotal in addressing emerging challenges, such as the impact of aging populations on donor organs and the evolving landscape of infectious diseases.

In conclusion, the past 60 years have witnessed a transformative journey in LT, marked by pioneering achievements, advancements in medical science, and a commitment to improving patient care. From experimental procedures to routine clinical practice, LT has become a cornerstone in the field of organ transplantation, offering hope and extended life to countless individuals worldwide. As the trajectory of LT continues to ascend, it is essential to reflect on the progress made, acknowledge the challenges that lie ahead, and remain dedicated to advancing the frontiers of science, medicine, and patient-centered care in the years to come.