In situ liver transplantation was initially used for the salvage of patients with end-stage liver disease before it became routinely used for the salvage of patients with acute liver failure (ALF). Prior to the use of liver transplantation as a salvage measure, mortality rates in patients with ALF were as high as 80-85%. However, survival rates for liver transplantation in ALF were lower than in patients with elective transplantation. In the past 30 years, with the development of the field of liver transplantation and intensive care techniques, the 1-year survival rate after liver transplantation for ALF has been increased to 60-80%. As of 2010, the number of liver transplantation cases for acute liver failure in China accounted for 2.75%. Prognosis The survival rate of patients with acute liver failure in the natural course is only 15-20%, so it is important to quickly and accurately screen patients for emergency liver transplantation. Clinical mortality prediction may help distinguish those patients who are dying, but is not entirely reliable. In an organ shortage setting, it is also important to remove extremely critically ill patients from the transplant list who cannot undergo liver transplantation. Many predictive assessment models have been used to select appropriate patients for liver transplantation to minimize the number of patients who would otherwise not require transplantation facing unnecessary lifelong postoperative immunosuppressive therapy. However, these predictive models have many limitations and varying degrees of accuracy in predicting outcomes. Extant data suggest that many of the current predictive scoring models do not accurately assess the prognosis of acute liver failure and the indications for liver transplantation. The MELD scoring system is currently in common use. Clinical criteria Contraindications to transplantation vary among transplant centers, but generally include: age 70 years or older; certain extrahepatic complications; severe cardiac disease; pulmonary or multi-organ failure; severe infection; uncontrollable infectious shock; brain death; patients with the following clinical manifestations cannot be transplanted, including dilated fixed pupils, cerebral perfusion pressure <40 mmHg, persistent intracranial pressure (ICP) > 50 mmHg and patients at high risk for postoperative neurological complications and brain death. Transplantation may still be considered in patients with nonmotorized limbs but still responsive pupils. Brain edema Brain edema is a characteristic manifestation of hepatic encephalopathy (HE) in acute liver failure, and the mechanism is unknown. Cerebral edema occurs in approximately 80% of patients with grade 4 hepatic encephalopathy. Cranial hypertension due to cerebral edema further leads to ischemic brain injury or brain herniation, which accounts for nearly 50% of deaths in patients with ALF. Intracranial pressure monitoring is often used in patients awaiting transplantation and may even be further used extensively in patients with liver failure. The risk of intracranial hemorrhage complicating intracranial pressure monitoring is 10.3% and does not improve 30-day survival after transplantation. Therefore, the indications and timing for the use of intracranial pressure monitoring remain divided. Because cranial hypertension may persist 10-12 hours after liver transplantation, continuous intra- and postoperative monitoring with intracranial pressure is required. Infection Although patients with ALF are frequently complicated by infection, it is sometimes more difficult to diagnose. Patients often have typical ALF hemodynamic changes without elevated leukocytes or fever. 10-37% of cases die from bacterial infections. the incidence of fungal infections (especially Candida sp mother strains) approaches 32% late in the course of ALF, especially after the use of antibiotics, and is often combined with bacterial infections. Active bacterial or fungal infections are a contraindication to liver transplantation. The empirical use of antibiotic therapy is currently controversial. Prophylactic use of antibiotics may reduce the number of infections but does not improve overall prognosis. Some centers routinely use antibacterial and fungal therapy in patients with meaningful strains cultured, in patients with hepatic encephalopathy degree 3-4, in patients with uncontrollable hypotension, and in patients with clinical evidence of inflammatory response syndrome (SIRS). Psychosocial assessment The financial burden of long-term medication after liver transplantation can significantly affect quality of life. Therefore, there are many controversial issues that must be considered prior to performing liver transplantation. Examples include psychosocial factors (e.g., adequate social security and/or the presence of a history of alcohol abuse) and the availability of adequate health insurance coverage. As an example, in one survey, four patients (12%) died by suicide during postoperative follow-up. Prognosis of transplantation Post-transplantation survival Many contraindications to transplantation that arise with rapid progression of the disease can deprive patients of liver transplantation opportunities. This problem was demonstrated in patients with acute liver failure due to acetaminophen who met the criteria at King’s University Hospital London. 30% of patients were not listed for transplantation due to rapid onset of preoperative comorbidities, and 35% of those listed for transplantation were eventually removed due to rapid progression of disease. The majority of patients (90%) who met the criteria for transplantation but did not undergo transplantation eventually died. In a large US study, 29% of patients with ALF underwent liver transplantation, but 25% (10% of overall) of patients on the transplant list died before receiving an organ. In general, about 15-30% of patients died before liver transplantation was performed. The cause of death is mostly brain death, as well as other diseases such as sepsis, circulatory failure, multiple organ failure, and more commonly, upper gastrointestinal bleeding. Overall, post-transplant survival rates for ALF patients range from 60-80%, with most deaths occurring within 3 months post-transplant, usually due to neurological complications and sepsis. In the United Kingdom, the survival rates of ALF patients at 1 and 5 years after transplantation were 81% and 73%, respectively, with death occurring mainly within 2 months after surgery. On multivariate analysis, the main risk factor for the occurrence of high postoperative mortality was graft steatosis, commonly seen in donors with BMI >25 kg/m2. In Spain, Portugal, Belgium and Italy, the main causes of acute liver failure were hepatitis B infection and cryptogenic disease. Their 1-year postoperative survival rate is 61-79%. In the United States, the 1-year postoperative survival rate has increased from 73% to 82% and the 1-year survival rate after grafting has increased from 63% to 75% over the past 10 years. Factors affecting postoperative survival include recipient age >60 years, donor age >60 years, and mechanical ventilation therapy during transplantation. Multi-organ failure Severe multi-organ failure during transplantation significantly affects post-transplantation survival. In patients with non-acetaminophen-induced liver injury, diminished renal function was significantly associated with poorer natural survival. In a multivariate analysis study of UNOS data from 1988 to 2003, four risk factors were summarized as predictive of post-transplant survival: history of life support treatment; recipient age >50 years; recipient body mass index ≥30 kg/m2 and blood creatinine >2 mg/dl. If a patient had all four risk factors together, the 5-year post-operative survival rate was only 44 -47%. If none of these risk factors are present, the 5-year survival rate is 82-83%. Liver transplantation options Depending on the donor, various transplantation options are available: cadaveric donor, living split donor, ABO-matched condition, and assisted liver transplantation. Given the shortage of organs, the pros and cons of using marginal grafts resulting in complications and the risk of non-functionality versus the risk of waiting for transplantation should be carefully weighed. Living Liver Transplantation In living liver transplantation, it is important to adequately assess the recipient’s required graft volume and adequate donor residual volume. Patients with a graft-to-recipient weight ratio greater than 0.8% have a better prognosis, with a more favorable outcome if 1.0% is achieved. Within four weeks after transplantation, the grafted liver and the residual donor liver can grow to their original size. The survival rate at one year after pediatric living liver transplantation is 67-89%, and the mortality rate while awaiting transplantation decreases to 9%. Of the pediatric liver transplants performed by SPLIT, 57% of children with ALF received partial donor transplants and their prognosis did not differ from that of children who received whole liver transplants. Adult human living liver transplantation is primarily used in patients with cirrhosis, with a 3-year postoperative survival rate of 73-90%. The use of right hemi-liver grafts in adults has a higher success rate due to their larger size. The exact graft volume required for successful recovery is not clear, but requires a minimum equivalent of 35%, if not up to 50%, of the standard pole liver volume. This means that left hemi-liver grafts are usually only indicated for pediatric patients, while most adults require right hemi-liver grafts, thus increasing the surgical risk for the donor. Complications of right hemi-liver transplantation (15-20%) are more frequent than those of left hemi-liver transplantation (10-15%). These include bile leaks, hematomas, and incisional infections. Based on single-center data showing that despite the absence of early and distant donor death, the complication rate was 8% for left hemi-liver donors and 32% for right hemi-liver donors, with significantly fewer complications for left hemi-liver donors than for right hemi-liver donors. A mortality rate of 0.2% has been reported for right hemi-liver donor donors. The experience of performing living liver transplantation in ALF patients is even more limited. In Japanese and Korean reports, the overall 1-year survival rate is approximately 59-90%. There are special ethical issues associated with living liver transplantation. These include ensuring the safety of the donor, avoiding forced donation, and whether there is broad family acceptance of donation in emergency situations. Because of the rapid progression of ALF patients, the otherwise very detailed medical and psychosocial aspects of the donor-related evaluation must be kept as simple as possible. The pressure of public opinion led to opposition to live liver transplantation for ALF patients at the 1997 EU Council meeting and to a commitment to provide donors for liver transplantation in the first instance for such patients. In areas where cadaveric donors are not widely available, it is important to weigh the risk to the recipient while waiting for donor surgery against the magnitude of the risk of performing living liver transplantation. It is particularly important that a bill clarifying this relationship be developed as soon as possible. Adjuvant liver transplantation Adjuvant liver transplantation refers to the use of a portion of the donor’s liver to be implanted in the recipient as a temporary adjunct to treatment while retaining the recipient’s own damaged liver. The recipient’s own liver can be taken off immunosuppressive drugs after recovery, and the graft can be surgically removed or allowed to shrink naturally. The adjuvant graft can be placed underneath the recipient’s own liver (ectopic adjuvant liver transplantation) or after removal of a portion of the diseased liver (left or right half) and placed within it (in situ adjuvant liver transplantation). Alloadjuvant liver transplantation is simpler, but the inferior hepatic vena cava anastomosis may cause outflow tract obstruction and reduce hepatocyte regeneration to the point where residual necrotic liver tissue may release cellular damage factors. There is a higher incidence of primary nonfunctionality and portal vein thrombosis in allograft-assisted liver transplants compared to in situ assisted liver transplants and in situ whole liver transplants. Adjuvant liver transplantation for the treatment of patients with hepatitis B is controversial due to the potential for graft reinfection; patients with Willson’s disease and Budd-Chiari syndrome have a poor prognosis with adjuvant liver transplantation. Younger patients with acute viral or autoimmune liver disease have a better prognosis with adjuvant liver transplantation, but these patients also have a good chance of natural recovery. The overall survival rate for adjuvant liver transplantation has been reported to be 63%, and 2/3 of these recipients can be tapered off immunosuppressive therapy. A controlled study conducted in Europe of 47 adjuvant and 384 conventional liver transplant patients showed roughly similar overall 1-year survival rates in both groups (62% and 61%, respectively). However, the 1-year survival rate was 71% for patients with in situ adjuvant liver transplantation and only 33% for patients with allogeneic adjuvant liver transplantation. Compared to conventional liver transplantation, adjuvant liver transplantation has more postoperative complications, including biliary and neurological problems, despite essentially identical postoperative survival rates. Recipient liver regeneration as well as graft function are diminished due to the greater flow of portal blood to the graft. Quality of life Despite subtle differences, overall long-term survival and quality of life after liver transplantation in ALF patients remains very good. A controlled study of seven ALF liver transplant patients versus chronic liver disease liver transplant patients showed that both groups complained of different impairments on neurophysiological tests, but ALF patients had more focused complaints and lower scores. The King’s University London study group administered questionnaires to a small group of ALF transplant patients 2-3 years postoperatively and chronic liver disease transplant patients. The ALF group had mildly lower mental health scores (68% versus 79%; P=0.022), possibly due to the lack of systematic pre-transplant education and pre-transplant counseling in the ALF group. There was no significant difference between the two groups in terms of lower quality of life scores. The functional status of the body organs as well as the mental-emotional domain was mildly diminished in ALF liver transplant patients compared to normal, but similar to liver transplant patients with chronic liver disease. In an in-depth investigation, six ALF recipients had reduced exercise and frequent fatigue during the first 3 to 6 months after transplantation, resulting in weight loss and loss of muscle and bone mass. During this period, the patients were still dependent on others for care, but all felt continued improvement in their own health. They gradually regained independence in their own lifestyle. Team assistance and role modeling were very helpful in overcoming difficulties. Most of the patients felt that they had a “second life” and were more willing to support other patients in the same treatment. Conclusion Medical advances have improved the prognosis of ALF patients after transplantation. Although predictive models have been very helpful in the management of ALF, there is still no fully accurate model for the assessment of indications for emergency liver transplantation. In an environment of organ shortage, unconventional liver transplantation is increasing, including living split donors, ABO blood group incompatible donors, and adjuvant grafts, with variable prognosis. The pros and cons obtained by the recipient and the donor must be carefully weighed. Long-term survival and quality of life are better for donor-recipients, but extended postoperative monitoring helps identify those who are depressed. Evolving new techniques will greatly improve the short- and long-term prognosis of patients with acute liver failure.