Recent advances in understanding and managing liver transplantation

Extended criteria donors

Although the definition of an extended donor has not been thoroughly established, most agree that it conveys a higher risk of either physiologic dysfunction or infectious/metabolic disease transmission. Extended criteria can be separated into two groups: donor-related risk factors and surgical technique-related issues. Donor-related issues include donation after cardiac death (DCD), advanced age, increased cold ischemia time, ABO incompatibility, steatosis, previous malignancies in the donor, hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, human T-cell lymphotrophic virus type I/II infection, or other active infections. These extended criteria donors can generally be accepted or declined by the transplant team during evaluation of the allograft. Surgical technique-related issues of extended donors include split LT (SLT) and partial grafts used in living donor LT (LDLT). Both of these methods can provide a graft when a whole cadaveric organ is unavailable⁵. In the first group, a special mention needs to be made for DCD, whereas amongst the latter we will address the SLT procedure and LDLT.

Donation after cardiac death. DCD organs are expected to expand the donor pool. Indeed, in the past 10 years in the US, 2,710 liver donors have been DCD organ donors, with the largest numbers used in the last 2 years⁶. Although previous experiences with DCD have been associated with greater risk of graft failure⁷, more recent reports did not confirm this finding, showing similar outcomes between DCD and donation after brain death (DBD)⁸. Still, some limitations need to be considered by the transplant team. In order to ensure a similar outcome to those associated with DBD, several variables need to be taken into account, such as donor age, warm and cold ischemia times, and duration of donor hypotension or hypoxemia^9–11. Hopefully, in the next few years, improving our ability to perform ante mortem interventions will improve the likelihood of successful donation and graft outcomes. On the other hand, post mortem intervention such as the use of machine perfusion (MP) systems to improve graft function during the preservation period will be an additional challenging issue to improve DCD utilization. MP indicates several dynamic strategies applied ex vivo of organs for transplantation that aimed to improve the static cold storage preservation¹². Recently, De Carlis et al.¹³ reported their experience in using the MP in the setting of DCD. Even if the relatively small sample size (7 cases) limits the general applicability of the results, patient and graft survival were both 100% after a mean follow up of 6.1 months (range 3 – 9) and no cases of ischemic cholangiopathy occurred during the follow-up. Hopefully, the extensive use of MP will lead to a significant increase of the availability of transplant livers as well as a significant reduction in several types of graft dysfunction and biliary complications.

Split liver transplantation. Over the 25 years since the first LTs were performed¹⁴, in light of continuing organ shortages and growing numbers of patients dying whilst waiting for transplants, SLT enlarges the donor pool and is one of the few surgical options to do so. LT performed with split grafts in Europe and in the US accounted for about 6% in the past decade¹⁵. Although the outcomes of LTs performed using partial grafts are good, there are specific complications associated with this technique. For example, small for size syndrome, related to a reduced ratio between graft and recipient body weight, is characterized by prolonged jaundice, graft dysfunction, and sometimes graft failure. Favorable results with SLT depend on not only the technical factors but also scrupulous recipient and donor selection.

Living donor liver transplantation. LDLT has emerged as a promising alternative to overcome donor shortage¹⁶. The improvements in LDLT have led to the expansion of the recipient criteria to include patients previously considered not suitable for LT because of older age or co-morbidities. Living donors older than 45 years are often discarded, since the risks of these LDLTs remain controversial. Goldaracena et al.¹⁷ compared patients receiving a LDLT from 91 donors aged ≥50 years with 378 younger than 50 years. The incidence of biliary complications as well as graft and patient survival at 1, 5, and 10 years were similar between both groups. Similarly, Oezcelik et al.¹⁸ evaluated the use of LDLT in recipients older than 70 years. No significant differences in complications, hospital stay, perioperative mortality, or median survival compared to the younger group were found. Although LDLT is not a “100%” safe procedure and donor death rate has been reported around 0.1–0.3% (possibly reaching 0.5% when using the right hemiliver for adult-to-adult transplantation)¹⁹, the understanding of the biochemical mechanisms of graft injury and the possibility of promoting liver regeneration will be the key issues for the improvement of the use of partial liver grafts.

Chronic liver diseases

During the assessment of a patient with liver disease, signs of decompensation (jaundice, moderate to severe ascites, previous variceal hemorrhage, or hepatic encephalopathy), suggest the need for a referral for evaluation for LT²⁹.

The ideal timing for performing LT should be balanced between mortality rate while on the waiting list and perioperative and postoperative mortality (10–15% at 1 year and 15–25% at 3 years)³⁰. This decision must take into account both quality of life and prognosis related to natural history of liver disease as well as post-surgical mortality and morbidity. For these reasons, patients should be strictly selected and prioritized using prognostic scores. Currently, severity and mortality with liver disease is best highlighted by the MELD (model for end-stage liver disease) score, which predicts a recipient’s survival within 6 months through a logarithmic scale that includes as the variables a patients total bilirubin, INR, and creatinine.

However, the MELD score without modification was shown not to adequately reflect all of the complications of portal hypertension (e.g. hepatic encephalopathy and severe ascites). Thus, some efforts to update the prognostic value of the MELD score have been made over time. The MELD-Na formula (which added serum sodium to the abovementioned biochemical parameters)³¹ is now the most used formula to predict survival among candidates for LT, especially for those with significant portal hypertension.

The MELD-based model applied a "sickest-first policy" and was adopted for use for graft allocation in US by UNOS in 2002 and in Europe by Eurotransplant in 2007. In a large study, LT candidates with a MELD score ≥18 demonstrated considerable transplant benefit, while those transplanted with a MELD score <15 showed a higher mortality rate when compared to those still waiting for transplant³².

Hepatocellular carcinoma

HCC is one of the common indications for LT worldwide. About 20 years ago, the Milan criteria (MC; three nodules <3 cm or a single nodule <5 cm without vascular invasion) were proposed to select patients with HCC achieving the best survival after LT. Patients within the MC had a 5-year survival of about 70% with a tumor recurrence of <10%³³. This survival matches the post-transplant survival of most other indications for LT; therefore, the MC still represent the globally accepted score system to consider patients with HCC suitable for LT. However, modest expansion of the MC could increase the number of selected candidates for LT without negative impact on survival^34,35. Other authors recently proposed the evaluation of tumor behavior as a criterion for listing³⁶. Even though the MC remain the preferred model to allocate organs to patients with HCC, because of the excellent post-LT survival, a modest expansion of these criteria could be one of the future challenges for transplant hepatologists in the next decade³⁷.

Acute liver failure

ALF is a clinical manifestation of sudden and severe hepatic injury, mainly characterized by the onset of hepatic encephalopathy and severe coagulopathy³⁸, being caused by a massive necrosis of liver parenchyma exceeding the so-called minimum "critical mass" of hepatocytes capable of preserving organ function³⁹. The most important etiological factors of ALF are viral infection (mainly HBV), drugs (mainly acetaminophen but also herbal compounds, non-steroidal anti-inflammatory drugs, antibiotics, and statins). Other less common causes are severe AIH, Wilson’s disease, mushroom poisoning, and toxic substance consumption (e.g. ecstasy, MDMA, and cocaine). In a significant percentage of patients, no etiological factor can be found, especially in the pediatric population⁴⁰. The timing of encephalopathy onset is crucial to establishing the type of ALF (e.g. hyper acute, acute, or subacute) and to providing an adequate short-term prognosis. Different selection criteria for emergency LT are used worldwide. Commonly used criteria evaluate multiorgan impairment (encephalopathy and metabolic acidosis), etiology, and severity of coagulopathy as the most important factors for listing ALF patients. King's College criteria⁴¹ are the most commonly applied; however, other algorithms have been proposed over time^42,43. Nevertheless, several factors, such as recipient age, severity of pre-transplant illness, comorbidities, and the nature of graft used, could affect the outcome of emergency LT³⁸.