Deceased by Brain Death Liver Transplant vs. Living Donor Transplant/Putting Deceased Donor on Pump

Abstract

A written discussion of deceased by brain death vs. living donor and the use of the pump in deceased donor in liver transplant. Overview of living donor evaluation and potential contraindications to living donor liver transplant. Include a brief discussion on expanded donors in deceased donor liver transplant including steatotic livers and livers from donors of advanced age. It could also include a discussion on deceased by cardiac death liver transplant donation and potential complications from utilizing expanded criteria donors. Comparison of outcomes, advantages, and disadvantages between deceased by brain decath (DBD) and living donor transplant. Describe how the use of a pump expands the use of available livers. Also, review mechanisms of available pump technologies.

1. Introduction

Liver transplantation is a life-saving procedure for patients with complications of end-stage liver disease and stage T2 hepatocellular carcinoma. In 2017, deaths due to cirrhosis constituted 2.4% of total deaths globally, a rise from 1.9% in 1990. Leading causes include hepatitis B, hepatitis C, alcohol-associated liver disease, and non-alcoholic fatty liver disease (NAFLD) [1]. On the other hand, hepatocellular carcinoma is the sixth-most frequent new tumor, with more than 800,000 new cases diagnosed yearly and over 900,000 deaths every year, making it the fourth most common cause of cancer death [2]. The burden of these diseases makes the supply of liver organs for transplant outstrip the demand. The greatest challenge lies in the fact that there are not enough livers for all the potential patients that could benefit from liver transplantation. Today, in the United States, there are around 10,500 patients on the waiting list for liver transplants. Yet only 7000 liver transplants were performed in 2023. In 2017, >14,000 patients were on a waiting list, and only 8000 transplants were performed [3].

The consequences of being on a waiting list are not entirely favorable, with a mortality rate of 20–25% of waitlisted patients. A lengthy period of waiting can lead to further disease progression and debilitation before a transplant can be performed. Furthermore, severe deterioration can lead to the inability to perform the transplant and reserve the organ for other patients who might get the best outcomes [4].

It is well-known that most organs for transplantation are procured from deceased by brain death (DBD) donors. However, several challenges have emerged as the demand for liver transplants continues to rise and outweighs the supply. Improvement in safety, fortunately, has decreased the number of severe head injuries in young fit adults who used to be suitable DBD donors [5]. Furthermore, there has been an increase in the donor pool from an aging population with multiple co-morbidities. These challenges led to a shift in the paradigm to increase the donor pool. In the United States, there has been an 18% increase in liver transplant rate in the past 5 years, with the bigger proportion of the increase occurring among living donors, higher-risk donors as donation after circulator death (DCD), and the use of marginal grafts that carry technical challenge given age or risk of transmission of infection or malignancy [6]. Distinct types of liver transplants, outcomes, challenges, and future prospects will be discussed in this chapter.

2. Organ procurement

With the increased demand for liver transplants, proper organ procurement from a deceased donor remains an especially crucial step for a successful liver transplantation. Brain death is associated with various hemodynamic changes including hormonal, metabolic, and inflammatory changes in body organs. These changes might lead to increased immunogenicity and a higher risk of graft rejection. Hence, the optimal management of the organs might ensure their optimal function after transplantation [7]. The surgical technique for liver procurement includes warm and cold dissections. Warm dissection has the advantage of perfusion after identifying the vascular structures. However, the cold dissection technique might provide the benefits of shorter operation time and less organ damage through rapid procurement [8]. The classical method of preservation is keeping the liver in a basin that is filled with histidine-tryptophan-ketoglutarate solution (HTK). The first bag is sealed and placed in a second bag filled with cold normal saline or slushed ice, then placed in a third bag. The three-layered bag is finally placed in a heat preservation container box filled with ice for transportation [7]. New advances in liver preservation and transportation will be discussed later in this book chapter.

3. Overview of organ utilization

3.1 The use of marginal grafts

In the United States, one in four patients on the waiting list die before undergoing a transplant (12%) or become too sick to undergo liver transplantation (LT) (13%) [3]. This sad consequence of the disparity between the demand and supply of liver donation has emerged new prospects in expanding the donor pool and minimizing the rate of discarded organs. Central to these efforts is the liberalization of the acceptance criteria and use of the so-called “Marginal Livers” (MLs). Historically, that included livers that confer increased risk for poor graft and patient survival for various reasons including older age of donors (more than 70 years), DCD grafts, Viremic patients, livers split between two recipients, steatotic livers and the so-called “livers that nobody wants” which are livers that were initially declined by many centers before finally getting accepted by another center [9]. Listed Liver transplant patients who refused marginal organs have increased mortality risk compared to patients who accepted one [10].

3.2 Older age donors

Earlier data that looked at the utility of using marginal donors for liver transplantation associated older age (more than 70 years old) with worse outcomes and less chance for graft survival [11]. The explanation was that older livers have higher rates of steatosis, which might potentiate cold preservation injury. Some other data showed decreased adenosine triphosphate (ATP) capacity after reperfusion, which is thought to decrease the regenerative capacity [12]. This early data increased the aversion to elderly donors’ livers, and they are usually discarded [13].

A retrospective study by Halazun et al. [13] looked at the utilization of using older donors by looking at the outcomes of 3104 patients who received livers from donors more than the age of 70 years old. The authors demonstrated that although unadjusted outcomes of elderly grafts are inferior to those of younger donors, recipient factors like hepatitis c and prior surgery played a bigger role in impacting survival more than donors themselves. They further showed that cold ischemic time (CIT) is the only donor factor that impacted the outcome. Worse outcomes are associated with CIT time of more than 8 hours. The authors hypothesized that livers of older donors are underutilized.

Another systemic review looked at the outcomes in patients who received livers from octogenarian patients and showed non-inferior short and medium-term graft survival. However, they reported increased biliary complications [14]. Another cohort study looked at the trend of transplantation of liver grafts from older donors from 2003 to 2016. In 3350 liver-only recipients, the authors demonstrated that despite improvement in graft survival and decreased mortality, the rate of discarded organs increased [15]. These studies showed that it is reasonable to expand the donor pool by using grafts from older people [13, 14, 15].

3.3 Hepatitis C liver grafts

Historically, hepatitis C virus (HCV) viremic grafts used to decline and be discarded [16]. The development of Direct antiviral agents (DAAs) has revolutionized the treatment of HCV and consequently increased the potential of using HCV viremic grafts. A landmark clinical trial by Wooley et al. looked at the outcome of 44 adults without HCV who received heart or lung transplantation from HCV-positive patients. They initiated sofosbuvir-velpatasvir, A DAA regimen, preemptively a few hours after the transplantation and for 4 weeks. After 6 months, the authors demonstrated that 100% of the first 35 patients who received transplantation were alive with excellent graft survival and had undetectable HCV viral load [17]. A limitation of this study was the small number of patients enrolled. The American Association for the Study of Liver Diseases (AASLD) endorsed HCV viremic donors as an option for use by HCV-negative recipients [18]. A study by Cotter et al. in 2021 showed a 35-fold increase in HCV positive over 4 years, from 8 in 2016 to 280 in 2019. The author demonstrated excellent graft survival in one and 2 years. Furthermore, when adjusted for other recipients’ and donors’ attributes, HCV viremic grafts were not predictive of patient or graft survival [19].

3.4 DCD patients

Historically, organs were obtained from patients after cardiac arrest. In 1968, the committee of Harvard Medical School promoted the acceptance of brain death [20]. With that recognition, DBD gained widespread acceptance and constituted the majority of transplants. As the available pool of liver remains insufficient to meet the demands, DCD LT has grown to be an effective and acceptable mechanism to expand the donor pool and decrease waitlist mortality [21]. The utilization of DCD livers has increased more than sixfold, from 1.9% in 2002 to 12.1% in 2016 [22]. DCD LT differs from DBD donations based on the warm ischemic time (WIT), which is the time between cardiac death and organ cooling during procurement. The classification of DCD donors was originally described by the international workshop on non-heartbeating donors held in Maastricht in 1995. The classification included four categories, which are dead upon arrival, death after resuscitation, donors who are awaiting cardiac arrest, and cardiac arrest after brain death [23]. To further categorize donors who are expected to be exposed to a longer duration of ischemic time, the definitions of controlled and uncontrolled were added. The controlled definition included the first two categories [24]. A 2017 propensity-match study that compared the outcomes of liver transplantation between 300 DBD and DCD showed 5-year graft survival of 73.9% in DBD group versus 70.1% in the DCD group [25]. Another study by Abt et al. demonstrated that DBD liver transplant patients had better 1- and 3-year graft survival of 80.4 and 72.1% versus 70.2 and 63.3% in DCD LT patients [26].

Risk factors for donors that may lead to complications include donor age of over 50, weight over 100 kilograms, and warm ischemic time of over 30 minutes [27]. A retrospective review by Foley et al. looked at long-term outcomes of 85 patients who had DCD liver transplants and showed that CIT for more than 8 hours is a strong predictor for the development of ischemic cholangiopathy [28]. Recipients’ risk factors that might be more associated with complications include BMI of more than >30, hepatitis C positive recipients, and high model end-stage liver disease. Various complications have been associated with DCD LT, such as primary non-function, delayed graft rejection, and hepatic artery thrombosis [29]. A study by Croom et al. revealed that 25% of DCD liver transplants had biliary complications compared with 13% in the DBD group. A possible biliary complication is ischemic cholangiopathy [30]. Proposed methods to improve outcomes in DCD LT like machine perfusion will be discussed in detail later in this chapter.

3.5 Steatotic liver grafts

Given the pandemic of obesity and the increased prevalence of metabolic-associated dysfunction steatohepatitis (MASH), donor liver steatosis is becoming an increasingly common challenge that is facing the transplant community. The presence of moderate (more than 30% of Macro steatosis) has been associated with increased graft failure and primary non-function. However, the data has not been consistent [31]. Several studies showed that severe steatosis >60% has a higher risk of complications. A study by McCormack et al. demonstrated a higher rate of renal failure, long-term intensive care unit (ICU) stay (more than 21 days), and prolonged hospital stay (more than 40 days) in patients who received severely steatotic livers compared to the control group without severe steatosis. However, the sixty-day mortality and the 3-year patient survival rates were comparable [32]. Another study compared the outcomes between liver grafts with moderate steatosis and without steatosis after cardiac death showed that 90-day, 1-year, and 3-year survival rates in patients were similar (75 vs. 85.9%, 75 vs. 78.1%, 68.8 vs. 71.9%). The 90-day and 3-year graft survival were 75 vs. 84.4% and 68.8 vs. 68.8% between the two groups [33].

A meta-analysis in 2019 that looked at the impact of mild, moderate, and severe steatosis on liver transplantation showed there was no difference between mild and no steatosis groups in primary non-function (PNF) and early graft dysfunction. The PNF rate was significantly higher in moderately and severe steatosis than in the no steatosis group. However, graft survival and patient survival were similar in both groups. The authors concluded that liver with mild steatosis were safe liver grafts. Moderate and severe liver steatosis, although controversial, could produce a favorable outcome with strict protocols to keep CIT as short as possible, which might potentially expand donors’ pool of livers and provide a potential solution for this shortage [34].

3.6 Split liver transplantation

In Split liver transplantation (SLT), Donor livers are classically split into a smaller left lateral segment which is typically used for children LT, and a larger right tri-segment for adults. This led to a reduction in the pediatric waiting list mortality [35]. Further advancement enabled the use of two hemi-liver grafts, a left lobe (segment I-IV) and a right lobe (segment V-VIII), for transplant in two adult-sized recipients. This technique is underutilized, given technical challenges and the risk of reducing an excellent graft into two marginal grafts [36]. Initial experiences of split liver grafting showed increased morbidity and mortality in adult recipients [37]. A multicenter retrospective study compared the overall graft survival in situ split liver extended right grafts (SL-ERGs) between 1997 and 2004 and thereafter. The 1,3,5 overall graft survival was significantly higher in more recent transplantation. In multivariate analysis, the main prognostic factor of graft survival was a total ischemic time of less than 8 hours. The donor age of more than 60 years was associated with increased graft failure. The study suggested that SL-ERGs might not be considered as marginal grafts in experienced LT centers if appropriate precautions are taken in choosing appropriate donors [38].

More research is needed to investigate the outcomes of hemi-liver split liver transplantation. A multicenter study by Aseni et al. compared patient and graft survival outcomes between recipients who had an adult-to-adult split liver transplant (AASLT) compared with recipients of a whole graft. The study revealed a higher complication rate and inferior 5-year survival rate in SLT when compared with whole liver transplantation [39]. A recent study compared adult liver hemi transplantation (AHLT) versus adult with whole liver transplantation (AWHLT) in both patients with MELD scores of more and less than 30.

Among patients with model of end-stage liver disease (MELD) >30 and < 30, AHLT correlated with higher WIT, operative and hospitalization time, and intraoperative blood loss. In MELD score > 30, the 5-year survival year in the AWHLT group was significantly higher. However, there was no significant difference between survival outcomes in patients with MELD scores less than 30 [40].

Criteria for Split liver transplantation are strict, and only hemodynamically stable cadaveric donors are eligible for split liver transplantation. Criteria for left lateral splitting include age less than 55 years; fatty degeneration >30%; intensive care stay of less than 5 days; sodium level less than 160; serum glutamic pyruvic transaminase <60 U/L; gamma-glutamyl transpeptidase <50 U/L. The requirements are more strict when left/right full split is pursued with better outcomes when the donor age is less than 40, fatty degeneration is less than 10%, and ICU stay is less than 3 days [41].

A recent analysis of 37,333 liver transplants performed between 2010 and 2015 in the United States revealed that 2352 (6.3%) met the strict criteria of split liver transplant utilization. However, only 1418 livers (3.8%) were utilized for split liver transplantation. Two hundred ninety-nine children died on the waitlist who could have potentially benefited from split liver transplantation. The study suggested that split liver transplantation is an underutilized tool and should be promoted to decrease children’s waitlist mortality [42].

4. Organ preservation in liver transplantation

4.1 Novel techniques in organ preservation methods

The research in the field of Dynamic organ preservation goes back to the last century. Thomas E. Starlz, a pioneer of liver transplantation, performed an ex vivo liver perfusion of a chimpanzee in an attempt for liver transplantation without a favorable outcome [43]. Despite being a hot topic at that time, the revolutionary development of the University of Wisconsin solution provided a safe, effective, and simple method of liver preservation, leaving machine perfusion aside, given its higher costs and complexity. Since then, static cold storage has become the gold standard method of liver and other organ preservation [44]. With the expansion of the use of marginal grafts to bridge the gap between the demand and available organs for liver transplantation, the need for reliable measures to assess liver quality prior to transplant has emerged. This has led to the development of new strategies of dynamic preservation, mainly aiming to improve organ viability, extend preservation time, and assess organ quality. The efforts in the development of machine liver perfusion were resuscitated [45].

There are two important distinguishing factors in liver machine perfusion, one is the temperature, and the second is the approach. The perfusate’s temperature has a detrimental effect on the rate of metabolic functions in the liver, which is crucial for the intended metabolic effect. The first hypothermic liver machine perfusion device was introduced in humans in 2004 [46]. Liver perfusion in hypothermic conditions (below 12-degree Celsius) leads to a significant suppression of metabolic demands. The need for oxygenators versus perfusate oxygen was studied extensively, with the data revealing the clear metabolic need for oxygen during hypothermic conditions but at a low level. The perfusion during hypothermic machine, perfusion can be done via portal vein or dual perfusion through the portal vein and hepatic artery. In 2016, a study by Schlegel et al. revealed that a portal vein-only approach might be sufficient for hypothermic machine perfusion in DCD liver grafts [47].

In contrast, normothermic liver perfusion requires a very high metabolic demand with full availability of physiologic oxygen requirements and nutrients to keep the liver viable. In terms of achieving this level of perfusion, the machines are more complex and require dual perfusion lines for the portal vein and hepatic artery with readily available sensors for the metabolic demands and oxygen levels. Normothermic or sub-normothermic perfusions require red blood cells or artificial oxygen carriers, in contrast to the hypothermic oxygenated perfusion (HOPE) performed with high perfusate oxygen concentration. The first human application for normothermic machine liver perfusion was introduced in 2012 [48].

There are two main ex-situ perfusion approaches for livers that are essentially different in terms of timing and protective mechanism. The first method is the upfront machine perfusion immediately after procurement to replace classical cold static preservation. The organ in this approach is placed in a transportable device and undergoes continuous perfusion until the organ arrives at the recipient center and implantation occurs. This method requires complex and expensive systems to be used with blood products as the perfusate and typically includes normothermic or sub-normothermic perfusion [49]. A modification of this method is the normothermic regional perfusion (NRP), where perfusion is started earlier after the patient’s cardiac arrest and cannulation. The perfusion is done in situ with the donor’s blood for 2-4 hours before a decision is made regarding the procurement of the liver according to the liver enzymes and lactic acid values. This process aims to minimize the cold ischemic time [50].

The other liver machine perfusion approach is different in timing. It is usually applied after organ transportation at the recipient center. In this end-ischemic approach, the organs are usually perfused for a short time before transplantation using hypothermic, normothermic, or a combination of both in a process named controlled oxygenated rewarming. These techniques are less complex and less logistically challenging than upfront machine perfusion because there is no transportation of the machine perfusion device. However, it exposes the organ to a longer cold ischemic time, and subsequently, there is a risk for severe metabolic derangements, especially in higher-risk grafts [51].

4.2 Outcomes of transplantation after machine perfusion

As mentioned above, LT after DCD carries the risk of biliary complications including non-anastomotic biliary constrictions with studies showing cold ischemic time as an important factor in developing such complications [28, 29]. Machine perfusion transplantation aimed to decrease cold ischemic time and then decrease complications. Pre-clinical studies have shown that 2 hours of hypothermic machine perfusion (HMP) can restore mitochondrial functions and decrease the production of radical oxygen species that might damage the cells before transplantation [52].

The first clinical series done in human liver transplantation after hypothermic machine perfusion was done in 2010 by Guarrera et al. Transplant outcomes of 20 adult patients who received HMP-preserved livers were compared to a matching group of patients who received transplantation of livers after conventional cold storage. Early allograft dysfunction was seen in 5% of the HMP group and 25% in the control group, but the results were not statistically significant. Serum injury markers and hospital stay duration were significantly lower in the HMP group. This small, controlled pilot study demonstrated safety and feasibility and subsequently warranted further multicenter trials [53].

In 2017, Van Riijn and his colleagues completed a non-randomized controlled trial where they matched ten patients who received end-ischemic DHOPE-DCD (dual portal vein and hepatic artery hypothermic oxygenated machine perfusion of DCD liver grafts) to 20 patients who underwent static cold storage in the same center. Patients were matched for age, MELD score, and warm ischemic time and were followed for a year. The DHOPE recipients had statistically significantly lower alanine transferase (ALT) and gamma-glutamyl transferase (GGT). The one-year survival rate for patients and grafts was 100% in the DHOPE recipients. Five patients in the static cold storage group required retransplantation for non-anastomotic biliary stricture, while none of the DHOPE treated livers required retransplantation. However, this result was not statistically significant. The authors noted a significantly higher incidence of hypokalemia in the DHOPE group. This study was challenged by the very small number of patients and the use of historical controls [54].

In 2019, Schlegel et al. looked at the long-term outcomes (5 years) of DCD liver transplants after donor organs had been treated with hypothermic oxygenated perfusion. The study compared 50 hope-treated DCD patients from Zurich to 50 DBD patients and 50 untreated DCD patients from the United Kingdom. The patients were matched for recipient age, cold ischemic time, and low MELD scores. The overall donor-recipient risk based on the UK DCD risk score was higher in the hope-treated patients given older donor ages and longer warm ischemic time. Despite the higher risk, hope-treated DCD patients achieved a similar graft survival outcome to the standard DBD transplants. The number of non-anastomotic strictures (NAS) was more than double in the untreated DCD group compared with the hope-treated group. Graft loss due to non-tumor causes occurred in 4 out of 50 patients in the hope-treated group compared to 16 patients in the untreated group. (8 vs. 32% with a P-value of 0.005). On a sub-group analysis censored for tumor death, the five-year graft survival was 94% in hope-treated grafts vs. 78% in untreated grafts (P = 0.024).

The study had some limitations; 70% of the recipients in the hope-treated group had hepatocellular carcinoma, and the exclusion of tumor-related graft failure could have potentially skewed the results. The perioperative protocols were different in both centers between Zurich and Birmingham. In addition, the immunosuppressive regimen was also different. These differences need to be considered and can present a limitation for the clinical significance of this trial [55].

In 2021, Czigany et al. conducted a prospective, multicentric, randomized controlled trial where 46 patients DCD LT patients were assigned to HOPE vs. static cold storage (SCS). Peak ALT value after 7 days was the primary endpoint. The authors demonstrated a 47% decrease in peak serum ALT level in the Hope group. They also showed a significant reduction in the 90-day complications, with 44% in the Hope group vs. 74% in the SCS group, in addition to a shorter ICU stay. A trend of reduced early allograft dysfunction was observed in the HOPE group but was not statistically significant. The perioperative and immunosuppression protocols were similar and standardized between the two groups of this study; however, the participating centers used different surgical techniques per their local protocols [56].

In a multicenter-controlled trial, Van Riijn et al. randomly assigned patients who were undergoing transplantation from DCD patients to receive livers after DHOPE treatment vs. SCS. The study included 160 patients, of whom 78 patients were assigned machine-perfused livers, and 78 were assigned SCS livers. The study was conducted in six liver transplantation centers in Europe. The primary endpoint of the study was the incidence of symptomatic non-anastomotic biliary strictures after 6 months of the transplantation. The criteria for NAS were specified as narrowing or irregularity of the intrahepatic or extrahepatic donor bile ducts, seen using cholangiography in the combination of clinical symptoms or a cholestatic pattern of the liver enzymes. The images were interpreted by two different radiologists who were blinded to the allocation of the patients. NAS biliary stricture occurred in 6% of the DHOPE-treated group vs. 18% in the untreated arm (P = 0.03). The authors also demonstrated a reduction of 15% in the incidence of the post perfusion syndrome between the two groups, with 12% in the DHOPE group and 27% in the control group. In addition, early allograft dysfunction (EAD) occurred in 26% of the machine-perfused livers vs. 40% in the untreated livers. In this trial, the machine perfusion had no effect on the ICU duration stay, patients, or graft survival [57].

Normothermic ex-situ perfusion might give a chance to assess the viability of the liver before transplantation. In 2018, Watson et al. studied the characteristics of 47 liver perfusion, of which 22 resulted in liver transplantation. The authors demonstrated that liver viability during NMP can be assessed through a combination of lactate clearance, glucose release, maintenance of acid-base balance, and transaminase release. They also showed that PH can be a valuable prognostication for bile integrity. Bile PH measured in 16 out of 22 transplanted livers identified three livers that developed cholangiopathy, which was less than 7.4. Biliary PH was measured in 11 research livers; four achieved a PH of more than 7.5 and had minimal stromal necrosis of the intrahepatic ducts on histological examination [58].

The first randomized trial was completed in 2018 by Nasralla et al. In this trial, the authors compared normothermic machine liver preservation with the conventional cold static methods. Livers from DCD and DBD were included, and 334 livers were randomized between the two arms of the study. The primary endpoint of this study was the difference in serum aspartate transaminase (AST) within 7 days of the transplant between the two groups. Secondary endpoints included early allograft dysfunction (EAD), biliary strictures seen on MRCP after 6 months of transplant, hospital stay, graft survival and patient survival. The Peak AST after 7 days of transplant was reduced by 49.4% in the NMP group, disclosing a difference of 477 IU/L between the two groups. The rate of EAD was also significantly lower in the NMP. The study, however, failed to show a significant difference in biliary complications and patient or graft survival despite including mainly low-risk livers and choosing recipients of lower MELD scores. Another weakness is choosing AST as a primary outcome, which is a weak parameter of liver injury after transplantation [49].

In 2022, Quintini et al. demonstrated the role of enhancing graft preservation, extending viability by evaluating previously discarded livers. Twenty-one human livers declined for transplantation were enrolled to be assessed for normothermic machine perfusion. Livers were subjected to the proprietary device without issues. Six livers were ultimately excluded from NMP after failing to meet the criteria for transplantation with failure to clear lactate, limited bile production, or moderate macrosteatosis. Fifteen livers were transplanted successfully. No intraoperative or early major postoperative complication occurred in any of the recipients. No primary non-function occurred in any of the patients. Seven patients developed early allograft dysfunction but had fast recovery. Only one patient developed cholangiopathy in 4 months, and the rest of the patients had good liver functions with a follow-up time of 2 months to 14 months. The authors demonstrated that the viability criteria can be expanded. However, the study was done in one single center, and the small sample is a limitation for the reliability of the study [59].

Recently, Markmann et al. conducted a multicenter randomized controlled trial across 20 liver transplant programs in the United States. The trial compared the outcomes of 300 recipients of livers preserved using either normothermic machine perfusion or ischemic cold storage. The authors demonstrated a significant reduction in early organ dysfunction in the NMP group (18 vs. 31%). The NMP-preserved livers showed a significantly decreased incidence of ischemic reperfusion injury (6 vs. 13%). In addition, ischemic biliary complications were lower after 6 and 12 months in the NMP group. The 1-year graft survival rate was comparable between the two groups after 1 year [60].

5. Living donor liver transplantation

Despite the advancement in the field of liver transplantation, organ shortage remains an important challenge. Approaches to overcoming this issue include the use of marginal organs as organs from DCD patients, the use of machine perfusion in suboptimal grafts, and organs from patients who are infected with hepatitis C or HIV, which has been explained earlier in this chapter. With growing experience, living donor liver transplantation has become an established viable strategy to mitigate organ shortage.

Living donor liver transplantation (LDLT) may offer a chance of survival for patients with end-stage liver disease and hepatocellular carcinoma who are at a high risk of death while waiting for a suitable liver on the waiting list. Recent studies showed that LDLT could offer multiple theoretical advantages over DBD LT including shorter wait time and possible better graft quality [4]. A comparison of outcomes with DBT LT will take place by the end of this chapter.

The idea of LDLT was proposed as early as 1969 by Smith B., with the first attempt carried out by Raia et al. in 1989. The first successful LDLT was reported by Strong et al. in 1989 when they transplanted a liver from a living donor to her son in Australia [61]. Although the LT technique started earlier in the West, it quickly became the most common form of liver transplantation in Asia, with over 90% of the transplants performed using grafts that are commonly donated by relatives and friends. LDLT developed as a standard of treatment out of necessity due to the very limited number of deceased brain liver donors. The unique cultures, demographics, politics, and religion made the acceptance of DDLT remain limited despite its legalization in different countries [62].

LDLT has been considered a feasible and effective technique for decades, but it needs significant resource utilization and surgical expertise. In addition, donor safety, small size, and biliary complications remain major obstacles [63].

5.1 Donor safety in living donor transplant

Yee Lee et al. conducted a worldwide survey of the programs that perform LDLT to determine the incidence of mortality, morbidity, and near-miss events. The response rate was 48% (71 programs) that performed donor hepatectomy 11,533 times. They were able to give information regarding the case volume, demographics, graft types, morbidity mortality, and near-miss events. The study was able to generate reliable data demonstrating a morbidity rate of 24%, with 0.04% of patients requiring liver transplantation. The donor mortality was 0.2%, with most deaths occurring in the first 60 days after the procedure [64]. The adult-to-adult living donor liver transplantation cohort study (A2ALL) analyzed 760 donors. The no-go rate of donation was 2.6%, which was primarily due to findings in the operating room. The authors demonstrated a mortality rate of 0.4% and an overall complication rate of 40%. Serious complications that led to liver failure or death occurred in 1.1%. The most common complications included infections (12%), Biliary leak (9%), and incisional hernia in 6% of patients. The study suggested a trend of higher complication rates in left lobe donations, but the number of donors was very small (33 patients) which made the interpretation of the data challenging [65]. A study that looked at the quality of life for donors 11 years after donation using the health-related quality of life (HRQOL) surveys in living donors showed that they experience a higher quality of life compared to the general population [66]. Muzaale et al. followed up on 4111 livers in the United States between March 1994 and April 2003 and determined mortality using the Social Security death master file. The death rate was 1.7 per 1000 donors. The mortality of donors did not differ from healthy-matched individuals over a mean of 7.6 years. The rate of catastrophic events was 2.9 per 1000 donors, and five donors suffered from acute liver failure, where one improved, one passed, and three required DDLT salvage [67].

To maintain the safety and well-being of donors, LDLT centers have established strict criteria for selecting suitable donors. The donor age, degree of steatosis, and remnant liver volume (RLV) are important influential factors. The RLV should be fully functioning without venous congestion. In most LDLT centers, 30% of the total liver volume is widely accepted as a safety margin for minimal RLV [68]. Steatosis can affect the donor’s liver functions and ability to regenerate. Besides, it can affect the morbidity and mortality of recipients. There are no clear guidelines regarding the acceptable degree of steatosis for donation, but patients with more than 30% of steatosis are not accepted for right liver hepatectomy for safety concerns. However, the use of diet-treated donors might be feasible after their weight loss [69].

5.2 Statistics and indications

There have been more than 4600 adult LDLTs performed in the United States through 2015, constituting less than 5% of the total number of transplants performed annually. In 2013, 6455 liver transplantations were performed, all from deceased donors and only 252 (4%) from living donors. In the same year, among 166 liver transplant centers in the United States, only 43 centers performed living donor liver transplantation [70].

The organ allocation from deceased donors in the United States is based on the 11 regions of the United Network of Organ Sharing (UNOS), with the organ assignment mainly built around the MELD score except in some cases like fulminant liver hepatitis and liver primary non-function in the first week. The system allows for “the sickest first” policy where patients with the highest MELD score get priority. Exception points are given to conditions that may hasten mortality without a high MELD score, like hepatocellular carcinoma, cystic fibrosis, and hepato-pulmonary syndrome [71].

Given the current allocation system, LDLT Is generally indicated to patients with end-stage cirrhosis with complications like ascites without a high MELD score, hepatocellular carcinoma (HCC) patients who do not meet criteria for LDLT, or in regions where wait time would exceed 12 months; other indications include cirrhosis with a low MELD score but significantly decreased quality of life, cholestatic liver disease with a low MELD score and recurrent cholangitis [72].

5.3 Outcomes in living donor liver transplantation in comparison with DBD (Deceased by brain death) patients

The adult-to-adult living donor liver transplantation (A2ALL) study demonstrated survival benefits compared to staying on the wait list for DDLT. A2ALL is a consortium of nine liver transplant centers created to conduct retrospective and prospective studies that looked at the outcomes of both donors and recipients in the period between 1998 and 2008 [73]. A subsequent study in 2005 looked at the outcomes of 385 LDLT recipients and demonstrated ninety-day and 1-year graft survival rates of 87 and 81%, respectively. 13.2% of the grafts failed in the first 90 days. The most common complications included sepsis, primary non-function, and vascular thrombosis. The authors demonstrated that age and cold ischemic time are important predictors of graft failure. Interestingly, the centers that had a higher volume of cases (more than 20 LDLT) had significantly lower risk of graft failure [74]. Another subsequent study by Berg et al., looked at 868 potential recipients of LDLT, of whom 712 underwent transplantation. Overall, recipients had 56% lower mortality when compared to patients on the waiting list for DDLT. In patients without HCC, there was a mortality benefit in both groups of MELD scores of more and less than 15. In patients with HCC, a benefit was seen for patients with a MELD score of more than 15 but was not seen in the group with a MELD score of less than 15 [75]. A study by Goldberg et al. demonstrated that LDLT might be superior to DDLT when performed in experienced centers. The 3-year graft survival was higher in the LDLT group vs. the DDLT group (78.9 vs. 77.7%) [76].

Regarding hepatitis C recipients, a study demonstrated no differences between LDLT and DDLT groups in graft survival when the living donor transplantation is done in experienced high-volume centers that had more than 20 LDLT [77].

A recent study by Cotter et al. compared the UNOS data of 2566 LDLT patients with propensity scores that matched DDLT patients from 2010 to 2019. The authors demonstrated a doubling of LDLT from around 200 to 440 in 2019. One-year and 5-year graft survival in LDLT recipients was 88.4 and 78.1% compared with 92.5 and 80.7% in matched DBD patients. Older age, recipient diabetes, and the requirement of life support were associated with higher mortality and worse graft functions. The centers with the highest volume of LDLT per unit time had significantly superior outcomes in one-year graft survival [78].

LDLT can offer a clinically safe addition to deceased liver transplantation and can help decrease the mortality of being on a waiting list. Future surgical innovations and efforts to increase the living donor’s pool may foster the advancement of living donor liver transplantation in the United States in the future.

6. Conclusion

Liver transplantation has transformed the management of acute and chronic liver diseases. It is considered a life-saving procedure for patients with end-stage liver disease. Organ shortage remains a big challenge as the big burden of the disease makes the supply of liver organs for transplant outstrip the demand. Hence, to increase the donor pool, the use of marginal liver grafts has become an inevitable tool to overcome this shortage. These marginal grafts include grafts that historically conferred increased risk for poor graft and patient survival for various reasons including older age of donors (more than 70 years), DCD grafts, Viremic patients, livers split between two recipients, and steatotic livers. Several approaches have been developed to improve the outcomes of these marginal grafts. This progress is mainly aimed at decreasing cold and warm ischemic time. With the expansion in using marginal grafts, the need for reliable measures to assess liver grafts emerged. This has led to the development of new strategies of dynamic preservation, mainly aiming to improve organ viability, extend preservation time, and assess organ quality. Machine perfusion may allow for an increase in usable liver grafts and significantly improve outcomes. However, lack of financial support, knowledge, and difficulties in logistics are still important challenges for wider implementation. Living donor liver transplantation is another method to overcome the organ shortage that has been more developed recently with a subsequent increased rate of LDLT in the United States. LDLT may offer survival benefits for patients who are on the waiting list for liver transplantation. More research is required to further improve both donors’ and recipients’ safety and overcome technical challenges associated with LDLT. More studies to compare the outcomes of LDLT with DBD are needed to further delineate the risks and benefits for both donors and recipients.