key: cord-0970430-33ya8oce
authors: Kumar, Ramesh; Anand, Utpal; Priyadarshi, Rajeev Nayan
title: Liver transplantation in acute liver failure: Dilemmas and challenges
date: 2021-06-18
journal: World J Transplant
DOI: 10.5500/wjt.v11.i6.187
sha: f39715120d127eed112311e8871db25557264821
doc_id: 970430
cord_uid: 33ya8oce

Acute liver failure (ALF) refers to a state of severe hepatic injury that leads to altered coagulation and sensorium in the absence of pre-existing liver disease. ALF has different causes, but the clinical characteristics are strikingly similar. In clinical practice, however, inconsistency in the definition of ALF worldwide and confusion regarding the existence of pre-existing liver disease raise diagnostic dilemmas. ALF mortality rates used to be over 80% in the past; however, survival rates on medical treatment have significantly improved in recent years due to a greater understanding of pathophysiology and advances in critical care management. The survival rates in acetaminophen-associated ALF have become close to the post-transplant survival rates. Given that liver transplantation (LT) is an expensive treatment that involves a major surgical operation in critically ill patients and lifelong immunosuppression, it is very important to select accurate patients who may benefit from it. Still, emergency LT remains a lifesaving procedure for many ALF patients. However, there is a lack of consistency in current prognostic models that hampers the selection of transplant candidates in a timely and precise manner. The other problems associated with LT in ALF are the shortage of graft, development of contraindications on the waiting list, vaguely defined delisting criteria, time constraints for pre-transplant evaluation, ethical concerns, and comparatively poor post-transplant outcomes in ALF. Therefore, there is a desperate need to establish accurate prognostic models and explore the roles of evolving adjunctive and alternative therapies, such as liver support systems, plasma exchange, stem cells, auxiliary LT, and so on, to enhance transplant-free survival and to fill the void created by the graft shortage

The term "acute liver failure" (ALF) refers to a condition of severe hepatic injury that leads to altered coagulation and sensorium in the absence of pre-existing liver disease [1] . This disorder was first named fulminant hepatic failure in 1970, a term that has now been largely dismissed [2] . The main features of ALF are jaundice, coagulopathy, and hepatic encephalopathy (HE) while other features include cerebral edema (CE), susceptibility to infection, shock, and multi-organ dysfunction. Drug-induced liver damage is the commonest cause of ALF in developed countries while viral hepatitis tends to comprise the majority of ALF cases globally [3] . ALF is characterized by remarkably similar clinical characteristics, despite having diverse causes.

The mortality rates of ALF used to range between 80% and 85% before the liver transplantation (LT) era [4] . In recent years, however, ALF survival rates have greatly increased because of improvements in critical care management [1, 3] . Approximately half of the patients still die without emergency LT, and thus, LT plays a very important role in the management of ALF. However, LT is not widely available, and in most centers, ALF accounts for < 10% of the LT indication [5, 6] . LT is an expensive therapy that requires a major surgical procedure and lifelong immunosuppression. Intraoperative and post-operative treatments are challenging in ALF patients, and survival rates are consistently lower than those associated with elective LT. In addition, there is a need to balance the risks of emergency LT in ALF patients against survival with medical care alone. In order to choose suitable candidates for LT and prevent avoidable LT, it is necessary to have a prognostic model that can predict the outcomes early and very accurately. To date, while many clinical and laboratory parameters have been found to predict outcomes in patients with ALF, in terms of accuracy, early applicability, and ease of evaluation, virtually, none is close to optimal [7] . The rarity and heterogeneity of ALF have resulted in very few evidence-based management guidelines, and these guidelines essentially represent expert opinions. In this review article, the current dilemmas and challenges in the field of ALF have been addressed with regard to the therapeutic decision, and potential directions for further research have also been proposed.

In the early 1970s, Trey and Davidson originally identified ALF as a fulminant hepatic failure and defined it as "a severe liver injury, potentially reversible in nature and with onset of HE within 8 wk of the first symptoms in the absence of pre-existing liver disease"[2]. Many revised definitions have subsequently been proposed. There is, however, no definitive consensus to date. In addition, in clinical practice, diagnostic dilemmas are frequently caused by ALF-mimicking infections, uncertainty about the presence of pre-existing liver disease, confusion over HE, and variations in international normalized ratio (INR) testing.

A systematic analysis of 130 published ALF studies has identified a substantial variability in the definition of ALF. Over 81 studies have used 41 different ALF definitions, and no clear definition has been reported in the remaining 16 studies [8] . Currently, the most widely accepted ALF definition is "the occurrence of severe acute liver injury (ALI) with any degree of HE and INR of 1.5 or greater in a patient without pre-existing liver disease and a period of illness of < 26 wk" [9] . However, the icterusencephalopathy interval is still considered to be < 4 wk to describe ALF in the Indian subcontinent [10] . Such a wide diversity in ALF definitions hinders comparability among studies. Thus, there is an unmet need for a widely agreed definition of ALF in order to facilitate standardized clinical management and research in ALF patients.

The absence of underlying chronic liver disease (CLD) is a criterion for the diagnosis of ALF. Nevertheless, ALF is primarily a clinical diagnosis where the absence of CLD is presumed without sufficient investigation support. Radiological imaging may not detect early changes of CLD when a significant alteration in liver morphology is absent. In addition, a collapse of hepatic sinusoids, systemic vasodilation, and hyperkinetic circulation in ALF may contribute to the development of significant portal hypertension and ascites, making it difficult to rule out the underlying CLD [11, 12] . Differentiating ALF from the more common entity, acute-on-chronic liver failure (ACLF), can also become complicated at times in the real-world scenario. In a study carried out on 54 patients, the presumed clinical diagnosis of ALF has altered in 16.7% (9 out of 54) patients after transjugular liver biopsy [13] . On the other hand, there are some exceptions, such as Wilson's disease, autoimmune hepatitis, and Budd-Chiari syndrome, where ALF diagnosis is acceptable despite the presence of underlying CLD [1]. Also, there is no consensus-based clarity as to whether ALF or ACLF should be considered in patients with non-alcoholic fatty liver disease or chronic viral hepatitis who present with liver failure.

Jaundice, coagulopathy, and altered mentation that can mimic ALF may occur with many infectious diseases, such as dengue, malaria, enteric fever, leptospirosis, rickettsial infection, cytomegalovirus infection, herpes simplex virus infection, or tuberculosis [14] . However, the liver injury in these conditions is usually secondary. To allow a diagnosis of ALF, there should be a primary liver insult, and coagulopathy and altered sensorium should be attributed to liver disease per se, which can be difficult at times to decide. On the one hand, several non-hepatotropic viruses, such as dengue and herpes simplex, can cause severe hepatic damage leading to ALF, and on the other hand, common hepatotropic viruses can have mainly systemic manifestations of the extra-hepatic disease [15] . Such a diagnostic dilemma may not be so uncommon in the tropical world.

For making a diagnosis of ALF, HE is necessary to be clinically manifested. However, there is a lack of a well-validated and standardized assessment tool for early diagnosis and grading of HE. Several scales have been developed for this purpose, and the most often used is the West Haven criteria (WHC), which differentiate overt HE between four grades [16] . The subjectivity and considerable interobserver variability of the WHC, however, hinder low-grade HE assessments. 

INR has been developed as a tool to assess the efficacy of vitamin-K antagonist therapy. However, it is also used to assess the degree of coagulopathy in patients with 

Over the past 30 years, ALF has been transformed from a poorly known condition with a near-fatal outcome to one with a well-characterized phenotype and improved outcome. The ALF survival rate has improved dramatically in recent years due to a better understanding of pathophysiology and improvements in critical care management[1,3,4]. A substantial decrease in the incidence of CE and intracranial hypertension, a much-feared complication, has been observed over time, which may be attributed to earlier identification of the condition and better initial care [21] . The liver has an immense regenerative capacity, rendering ALF a potentially reversible disease in which survivors usually recover completely without sequelae. . While the improved survival rate on medical treatment has reduced the need for emergency LT in many patients with ALF, the challenge for the clinician to recognize patients who cannot live without a transplant has greatly increased.

Recognizing the feasibility of LT in ALF in the 1980s, the need for prognostic markers to determine the subset of patients most likely to benefit from this procedure emerged. In order to select an appropriate patient for LT and prevent avoidable LT, it is necessary to have a very precise prognostic model. The fundamental requirements of a prognostic model in the context of ALF are accuracy, early applicability, and ease of evaluation. When selecting a candidate for LT, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the prognostic model are important determinants. Sensitivity and PPV preferences ensure that all patients who require a transplant receive it whereas a preference for specificity and NPV minimizes unnecessary LT. From time to time, a large number of prognostic markers and models have been proposed so that patients predicted to have poor outcomes can be directed toward LT (Table 1 ). The King's College Criteria (KCC), Model for End-Stage Liver Disease (MELD) score, and Clichy criteria are the most commonly used and studied criteria.

The KCC developed in 1989 is the most thoroughly studied and widely used criteria. Owing to variations in the characteristics of parameters correlating with prognosis, the criteria are stratified into AALF and non-acetaminophen-associated ALF (NAALF). The performance of KCC was evaluated in patients with NAALF by a meta-analysis of 18 studies with data on 1105 patients [25] . The pooled sensitivity and specificity were 68% and 82%, respectively. This means that up to 32% of ALF patients who die may In a meta-analysis of 14 studies (n = 1960) evaluating the performance of the KCC in AALF, the pooled specificity was good (94.6%), but the pooled sensitivity was only 58.2% [26] . It has been proposed that the KCC should not be used as a static model but rather as a dynamic model. However, it is not clear at what point in time a decision on LT should be made. In a large prospective study from India, 25.7% of ALF patients died without meeting the KCC at baseline, and 42% of ALF patients who died never met the KCC by day 3 of hospitalization [27] . The poor performance of the KCC in that series could be due to the preponderance of viral etiology and hyperacute liver failure.

The KCC has been modified to incorporate other parameters, such as blood lactate and phosphate, in order to increase diagnostic accuracy. But the results are not so promising. Bernal et al [28] reported that the addition of post-resuscitation lactate concentrations (30 mmol/L) to the KCC improves the speed of identification, sensitivity, and negative likelihood ratio but decreases the positive likelihood ratio. While this will reduce the proportion of patients who die without being identified as transplant candidates, the proportion of patients who do not need LT may increase [28] . Schmidt and Larsen[29] reported that applying the blood-lactate-modified KCC in patients with AALF increases their sensitivity but reduces their specificity to < 50%, showing no clear advantages over the existing KCC [29] . Chung et al [30] reported that the addition of serum phosphate to KCC does not offer any significant advantages[30].

The MELD scoring system was initially designed to assess the probability of shortterm mortality in patients with cirrhosis. Subsequently, this score was also adopted to assess the mortality in patients with ALF and determine organ allocation by the United Network of Organ Sharing (UNOS) [31] [32] [33] [34] [35] . Yantorno et al [35] found that in 94% of ALF patients who died without LT, the MELD score was > 30 while it was < 30 in 91% of patients who survived with medical therapy alone [35] . Some studies indicate that the MELD score is superior to the KCC to determine the prognosis in patients with ALF [35, 36] , but many others do not [32, 33] . In a prospective trial assessing the performance of the MELD score in patients with AALF (n = 124), a score of 33 had sensitivity, specificity, PPV, and NPV of only 60%, 69%, 65%, and 63%, respectively. Moreover, to predict mortality, the MELD score was not superior to KCC or even INR alone [33] . Katoonizadeh et al [33] found that an MELD score of > 30 had a high NPV (91%) in NAALF patients, but the PPV was unacceptably poor (56%) [32] . A very high MELD score cutoff of > 35 discriminates between survivors and non-survivors with a sensitivity of 86% but with a low specificity of 75%[33]. Thus, the discriminatory cutoffs and predictive values of the MELD scores vary across the studies. In addition, various laboratory methods and reagents for the determination of bilirubin, creatinine, and in particular, INR can result in a considerable variation of the MELD score, thereby affecting its performance in routine practice.

In a recent meta-analysis of 23 studies (n = 2153) published between 2001 and 2015 that compared the accuracy of the KCC with MELD scores in predicting ALF mortality, none of the two scoring systems was optimal for all patients [37] . The KCC predicted hospital mortality more accurately among patients with AALF while the MELD score was better for NAALF. In patients with AALF, the diagnostic odds ratios (DOR), sensitivity, and specificity of KCC were 10.4%, 58%, and 89%, respectively, whereas the corresponding values of the MELD scores were 6.6%, 80%, and 53%, respectively. In contrast, for patients with NAALF, the DOR, sensitivity, and specificity of the KCC were 4.16%, 58%, and 74%, respectively, whereas the corresponding values of the MELD scores were 8.42%, 76%, and 73%, respectively.

In 1986, Bernuau et al [38] found that serum levels of factor V, alpha-fetoprotein, age, and absence of serum HBsAg were independent predictors of survival in a cohort of 115 patients with hepatitis-B-related ALF [38] . Originating from this study, Bismuth et al [39] used the so-called "Clichy criteria" to select ALF patients for LT at a liver center in Paris between 1986 and 1991 [39] . The criteria predicted poor prognosis in ALF when patients had advanced HE and factor V levels < 20% in patients < 30 years of age and < 30% in patients ≥ 30 years of age [39] . The Clichy criteria are mainly used in France to determine the prognosis of ALF patients. Subsequent validation studies, however, showed that the Clichy criteria were not only less accurate than originally stated but also less reliable to predict outcomes than KCC [40, 41] . A recent study evaluated the performance of Clichy criteria retrospectively in 808 adult ALF patients listed in France for super-urgent LT between 1997 and 2010. The sensitivity, specificity, PPV, and NPV were 75%, 56%, 50%, and 79%, respectively, for AALF, and 69%, 50%, 64%, and 55%, respectively, for NAALF [42] . In that study, 13.9% of listed patients withdrew from the waiting list because their condition improved subsequent to listing. The limited specificity and PPV of the Clichy criteria can increase the risk of unnecessary transplantation.

In ALF, hyperlactatemia may indicate the severity of the hepatic injury as well as multi-organ dysfunction [29] . A number of studies have shown that hyperlactatemia is associated with death or LT in both AALF and NAALF [26, 43] . However, there has been substantial variability in the timing of lactate measurements and fluid resuscitation procedures at different centers, making it more difficult to draw a uniform conclusion [43] . In AALF, where the duration of illness is short and multi-organ failure dominates the clinical course, the lactate level may have a better prognostic value. For NAALF, however, there are only a few studies with contradictory results available [44] .

The prognostic roles of non-liver-specific scoring systems, such as sequential organ failure assessment (SOFA) score and the acute physiology and chronic health evaluation II (APACHE II), are also assessed in ALF patients. In a retrospective study, the SOFA score was found to be prognostically superior to the MELD score at both 72 and 96 h after acetaminophen overdose [45] . In addition, a SOFA score of > 6 by 72 h post-acetaminophen overdose predicted death or transplantation with an NPV of 96.9%. In a prospective study on 102 ALF patients, an APACHE II score of > 15 had a similar power to predict death or LT as the KCC (sensitivity 82% or 65%, respectively, and specificity 98% or 99%, respectively). On the first day, an APACHE II score of > 15 was able to identify four more patients than the KCC [46] . More studies are needed to validate these findings before they can be used in routine practice.

The United States Acute Liver Failure Study Group (ALFSG) has developed a prognostic index for ALF based on the combination of clinical markers and levels of M30, an apoptosis biomarker [47] . In the ALFSG index, coma grade, INR, serum levels of bilirubin and phosphorus, and log(10) M30 values at study entry correctly identified patients, who would need an LT or die, with a sensitivity of 85.6% and specificity of 64.7%. However, the M30 measurement requires additional laboratory testing and costs. Moreover, this model was subsequently found to be inferior to the APACHE II and SOFA scores [48] . The ALF early dynamic model, which is based on dynamic values of arterial ammonia, serum bilirubin, INR, and advanced HE over 3 d, has been shown to have an excellent accuracy in predicting the outcomes of ALF patients [27] . The findings, however, require further confirmation. Similarly, the prognostic role of BiLE score, reduced monocyte HLA-DR expression, and arterial hyperammonemia requires further validation studies [49] [50] [51] [52] . Serum level of Gc-globulin also predicted mortality in patients with ALF but with poor sensitivity (49%) and NPV (43%)[53]. Serum phosphate concentration of 1.2 mmol/L at 48-96 h after acetaminophen overdose was found to be very accurate in predicting mortality; however, similar results could not be replicated in the subsequent studies [43, 54] . It was also found that the cytokeratin-18-based MELD score modification was better than the MELD scores and KCC, but there were no validation studies [55] .

While several prognostic scores have been established to predict outcomes in ALF patients, virtually, none are close to the ideal yet ( Table 2 ). The most prognostic models that are used worldwide today have features derived from analyses of historical patients treated without LT. In addition, in studies assessing the prognosis of ALF patients, there is gross variation in the definitions of ALF, etiologies, and management protocol. The survival rates of ALF patients on medical treatment have increased in recent years, but the models (e.g., the KCC and MELD) used are still the old ones [25] . Many studies have equated transplanted patients with non-survivors; this may falsely increase the PPV of prognostic scores. While some prognostic scores have shown better performance than the KCC and/or MELD scores, reproducibility and validation studies are lacking. Dynamic models are better than models based on 

The timing of LT is difficult to determine in ALF patients. ALF is a dynamic state in which the condition of patients can change very rapidly, making it difficult to predict the outcomes in the early course of the disease. A very late decision may result in a loss of opportunity to transplant, and a very early decision may lead to unnecessary LT (Figure 1 ). In the event of too early LT, the patients who would otherwise have survived with medical treatment would be subject to needless major surgery and lifelong immunosuppression, apart from major resource utilization and a loss of graft that could be used for another more suitable candidate. In the case of a very delayed decision, the patient may become too sick for LT, resulting in a potentially preventable death. The selection of timing for LT also depends on the probability of the potential for survival after LT. In a study from King's College Hospital, out of 310 ALF patients listed for emergency LT, 52 (17%) died before the organ became available, and 15 (5%) became too sick for LT. The death occurred at a median of only 2 d after listing [56] . Fortunately, the median time from listing to LT has now decreased to 1 d in some centers [57] .Pre-transplant waiting time of > 5 d was correlated with an increased post-LT mortality rate in one study by Yuan et al [58] . Therefore, a very limited window of opportunity appears to exist for LT in ALF patients, which could fall from day 2 to day 5 of admission. For better results, early applicability of prognostic models for listing and expedited donor evaluation will be essential. Dynamic models are better than models based on baseline parameters, but it is important to evaluate the crucial time at which a decision should be made. Criteria for LT should also take into account the waiting time, and once the graft is available, indication for LT should be reassessed in real-time. Another concern is the absence of well-defined delisting criteria while patients are on the waiting list. It is not clear what degree of clinical deterioration predicts LT futility in order to abandon a scheduled LT.

LT in ALF patients is associated with many ethical dilemmas. A pre-operative psychosocial assessment is a critical problem in ALF patients due to the presence of HE. In certain ALF patients, such as those with a history of acetaminophen overdose, alcohol abuse, or suicide attempts, such evaluation is necessary because there may be some risk of underlying psychological issues in them. In addition, knowledge of patients' financial and social support prior to LT is important. It can be difficult to predict compliance with post-LT treatment without a proper psychosocial assessment. The urgency of transplantation in ALF patients can result in the selection of unsuitable liver donors, and in the case of a living donor LT (LDLT), the fear of imminent death of the patient can easily influence the donor who is usually a close relative. A number of complications, such as biliary leaks, pleural effusion, bacterial infections, neuropraxia, incisional hernia, and venous thrombosis, are associated with donor hepatectomy [59] [60] [61] . Accordingly, the risk to the donor must be justified by the recipient's chance of recovery.

The post-LT survival rates of ALF patients have improved over the last three decades. The 1-and 5-year post-LT survival rates are 79% and 72% in Europe and 84% and 73% in the United States, respectively[6,62]. In a recent study based on 30-year single-center experience from Sweden, the 1-year, 5-year, 10-year, and 20-year post-LT survival rates in ALF patients were 71%, 63%, 52%, and 40%, respectively [63] . Between 2000 and 2014, the survival rates were even better (1 year-82%, 5 years-76%, and 10 years-71%).However, 1-year post-LT survival rate is still approximately 10% lower for ALF patients than for other transplanted non-ALF patients[6,62-64]. There is an increased risk of complications and mortality during the early post-operative period for transplanted ALF patients. Infections remain the commonest cause of early mortality after LT. Multiple factors affect the outcomes of patients transplanted for ALF (Table 3) . Among the causes of ALF, the best post-LT results are seen in Wilson disease whereas the worst results are seen in cases of drug-induced or autoimmune ALF [56, 65] . The prognosis of AALF is very distinct as survival with medical treatment is now approaching that of LT, creating a therapeutic dilemma in the management of such patients [66] . The age of the recipient has an important influence on the outcome of LT 

Therapeutic dilemmas may occur while deciding on LT in ALF patients with advanced HE, infection, or acute kidney injury (AKI). A study assessing the outcome of LT in ALF patients with grade 4 HE found a poor outcome unless LT was performed within 48 h of the onset of hepatic coma. In those LT performed after 48 h of hepatic coma, the 3-year survival rate was only 50% compared with 85% where LT was performed within 48 h [69] . If LT is completed within 48 h, a successful neurological recovery can be expected. It may not always be feasible, however, to perform LT within such a limited window of chance. Infection is very common in ALF patients, accounting for 37% of all causes of ALF mortality [70, 71] . Therefore, early and successful prevention and treatment of infection are of utmost importance. Approximately 5% of ALF infections are fungal infections, and a confirmed invasive fungal infection should preclude LT [71, 72] . AKI is very common in patients with ALF. In a study involving 1604 ALF patients, 70% were found to have AKI. While AKI reduced the overall survival time, the TFS rate was over 50% in patients with AALF or ischemic ALF, compared with 19% in patients with ALF due to other causes [73] . AKI is usually transient and is potentially reversible in ALF patients after LT. While AKI decreases post-LT survival to some degree, an LT should not be deferred because of AKI when other contraindications are absent [74] . However, there is a lack of robust evidence supporting and justifying the use of LDLT in ALF patients with AKI, and such a decision can only be taken on a case-by-case basis. The use of continuous renal replacement therapy (CRRT) can play a role in TFS or bridging LT in ALF patients with AKI[74]. In a recent study including 62 ALF patients, early institution of CRRT was found to be associated with the prevention of severe hyperammonemia and increased TFS compared with those without CRRT June 18, 2021

Volume 11 Issue 6 (55% vs 13%; P = 0.05) [75] .

An increasing global problem is the donor liver shortage, leading to a dilemma as to whether the sickest group of ALF patients should be prioritized. LDLT, auxiliary LT, and incompatible ABO graft can provide an alternative choice to solve the problem of organ shortages. In Asian countries, LDLT accounts for the bulk of LT [76] [77] [78] . However, inadequate time and expedited donor assessment for emergency LT could raise some concerns about the potential donor coercion, inappropriate donor selection, and increased risk of donor complications, including psychological problems in the donor. Between LDLT and deceased donor LT, the post-LT outcomes appear to be similar; the former, however, is associated with the risk of donor complications. In ALF patients, auxiliary LT may be an attractive alternative for providing temporary liver support until spontaneous hepatic regeneration takes place. However, since the procedure involves partial resection of the native liver in a critically ill patient and complex vascular reconstruction, the surgical technique is very challenging. There is, thus, not only a high risk of complications but also higher retransplant rates in auxiliary LT. In addition, it is difficult to predict which patients may develop native liver regeneration [79, 80] . Because of the pressing demand for grafts for ALF, incompatible ABO grafts have also been used. The early experience with incompatible ABO grafts was disappointing due to the increased risk of serious graft rejection, biliary complications, and vascular thrombosis. However, procedure refinements, including perioperative plasmapheresis, rituximab administration, splenectomy, and triple systemic immunosuppression, have resulted in better outcomes [81] . Such a protocol, however, needs full expertise and is related to an increased risk of complications, largely due to infection.

The current coronavirus disease 2019 (COVID-19) pandemic has had a major impact on surgical treatment for patients worldwide, including LT. Because of concerns about virus transmission, donor unavailability due to lockdown, and increased demand for intensive care unit beds for severe COVID-19 patients, many centers across the world have had to suspend their elective LT. There is concern that COVID-19 puts immunocompromised patients at a higher risk of morbidity and mortality. It is also presumed that post-LT immunosuppression may cause COVID-19 to be severe and long-lasting, though evidence for this is lacking [82] . Nevertheless, an emergency LT in ALF is a lifesaving procedure that cannot be refused due to COVID-19 issues. Extra caution is needed to avoid nosocomial COVID-19 infection among recipients, donors, and healthcare workers. The donors and recipients should be screened for COVID-19 before LT. Standard immunosuppression can be continued in the post-transplant period till further information becomes available [83] .

ALF is a devastating condition that may lead to the death of patients while awaiting a graft. Therefore, to provide a bridge to LT or spontaneous recovery, these patients may need an artificial liver support system. A variety of support systems, such as the molecular adsorbent recirculating system, the fractionated plasma separation and adsorption system, and the single-pass albumin dialysis system, have been developed over the last two decades. While these systems have been shown to have beneficial effects on different biochemical parameters, there is contradictory evidence on improved survival [84] . However, the careful use of these devices as salvage therapy cannot be questioned, given the shortage of available evidence from adequately powered randomized controlled trials. Warrillow et al [75] have recently reported the prevention of severe hyperammonemia and enhanced TFS in ALF patients with early CRRT [75] . High-volume plasma exchange therapy (HV-PET), defined as an exchange of 8%-12% or 15% of ideal body weight with fresh frozen plasma, has been found to improve survival in ALF patients [85, 86] . Larsen et al [85] in a randomized controlled trial (n = 182) found that HV-PET improves survival in ALF patients by 10% in comparison to standard medical therapy (58.7% vs 47.85%) [85] . Moreover, significant changes in hemodynamic and biochemical parameters are also noted. The efficacy of PET in ALF patients with acetaminophen or other drug/toxin-associated ALF is plausible, but further studies are needed to validate the efficacy of PET in NAALF patients where liver damage is mainly due to inflammatory and immunological processes. Even in the study by Larsen et al [85] , the majority of patients had AALF. In a recent meta-analysis, three studies on ALF reported improvement in outcome with PET [86] . In recent years, a growing number of studies have shown that stem cells can effectively treat liver failure. Mesenchymal stem cells (MSCs) are the most widely used stem cells to study liver diseases because they are easy to acquire without any ethical problems. Several pre-clinical and few clinical trials have shown that MSCs are capable of treating liver failure with short-term benefits, but there is no consistent long-term efficacy [87] . Therefore, it could be a promising field for potential studies to investigate the therapeutic role of stem cells in ALF.

LT is a lifesaving treatment for patients with ALF. Despite a substantial increase in survival rates after medical therapy, a little less than half the patients will die without a transplant. Nevertheless, there are several issues that complicate the therapeutic decision in ALF patients. An absence of reliable prognostic models hampers the selection of transplant candidates in a timely and precise manner. Sometimes, even a diagnostic dilemma happens due to the lack of a universally accepted definition. The shortage of graft, development of contraindications while on the waiting list, uncleared delisting criteria, time constraints, ethical concerns, and poor posttransplant outcomes are the other limiting factors. There is an unmet need for a widely agreed definition of ALF in order to facilitate standardized clinical management and research in ALF patients. Further study on disease pathogenesis and clinical course is needed to develop a more reliable prognostic model and identify new therapeutic targets with the aim to enhance TFS and limit the need for emergency LT.

Acute liver failure

MELD score to predict outcome in adult patients with nonacetaminophen-induced acute liver failure

MELD score as a predictor of liver failure and death in patients with acetaminophen-induced liver injury

MELD is superior to King's college and Clichy's criteria to assess prognosis in fulminant hepatic failure

Acute liver failure in Sweden: etiology and outcome

Ability of King's College Criteria and Model for End-Stage Liver Disease Scores to Predict Mortality of Patients With Acute Liver Failure: A Meta-analysis

Multivariate analysis of prognostic factors in fulminant hepatitis B

Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience

Emergency liver transplantation for acute liver failure. Evaluation of London and Clichy criteria

Comparison of the applicability of two prognostic scoring systems in patients with fulminant hepatic failure

French Liver Transplant Teams. Patients with acute liver failure listed for superurgent liver transplantation in France: reevaluation of the Clichy-Villejuif criteria

Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure

Hyperlactatemia in patients with non-acetaminophen-related acute liver failure

The sequential organ failure assessment (SOFA) score is prognostically superior to the model for end-stage liver disease (MELD) and MELD variants following paracetamol (acetaminophen) overdose

Earlier identification of patients at risk from acetaminophen-induced acute liver failure

Development of an accurate index for predicting outcomes of patients with acute liver failure

Accuracy of the ALFSG index as a triage marker in acute liver failure

Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure

Reduced monocyte HLA-DR expression: a novel biomarker of disease severity and outcome in acetaminopheninduced acute liver failure

Predictive value of arterial ammonia for complications and outcome in acute liver failure

Persistent hyperammonemia is associated with complications and poor outcomes in patients with acute liver failure

Acute Liver Failure Study Group. Gc-globulin and prognosis in acute liver failure

More on serum phosphate and prognosis of acute liver failure

Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury

Outcome after wait-listing for emergency liver transplantation in acute liver failure: a single centre experience

Acute liver failure: Summary of a workshop

Adult-to-adult living donor liver transplantation for acute liver failure in China

Donor complications among 500 Living donor liver transplantations at a single center

Outcomes of left-lobe donor hepatectomy for livingdonor liver transplantation: a single-center experience

Olthoff KM; A2ALL Study Group. Donor morbidity after living donation for liver transplantation

Liver transplantation for fulminant hepatic failure: experience with more than 200 patients over a 17-year period

Liver transplantation for acute liver failure -a 30-year single center experience

Outcomes following liver transplantation for seronegative acute liver failure: experience during a 12-year period with more than 100 patients

Fulminant hepatic failure: outcome after listing for highly urgent liver transplantation-12 years experience in the nordic countries

Timing and benefit of liver transplantation in acute liver failure

Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure

European Liver Transplant Association. 3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome

Living Donor Liver Transplantation in Acute Liver Failure Patients with Grade IV Encephalopathy: Is Deep Hepatic Coma Still an Absolute Contraindication?

Infection and the progression of hepatic encephalopathy in acute liver failure

Bacterial and fungal infection in acute liver failure

Epidemiology and risk factors for invasive fungal disease in liver transplant recipients in a tertiary transplant center

Acute Liver Failure Study Group. Risk factors and outcomes of acute kidney injury in patients with acute liver failure

Liver Transplantation for Acute Liver Failure in Presence of Acute Kidney Injury

Continuous renal replacement therapy and its impact on hyperammonaemia in acute liver failure

Liver and intestine transplantation in the United States

Outcomes after living donor liver transplantation for acute liver failure in Japan: results of a nationwide survey

Ethics and rationale of living-donor liver transplantation in Asia

Auxiliary partial orthotopic liver transplantation for fulminant hepatitis. The Paul Brousse experience

Auxiliary liver transplantation for fulminant hepatitis B: results from a series of six patients with special emphasis on regeneration and recurrence of hepatitis B

Successful long-term outcome of ABO-incompatible liver transplantation using antigen-specific immunoadsorption columns

Coronavirus disease 2019: Implications of emerging infections for transplantation

Liver transplantation and COVID-19 (Coronavirus) infection: guidelines of the liver transplant Society of India (LTSI)

Artificial liver support systems: what is new over the last decade?

High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial

Plasma exchange in patients with acute and acute-on-chronic liver failure: A systematic review

Progress in mesenchymal stem cell-based therapy for acute liver failure

Emergency adult-to-adult living-donor liver transplantation for acute liver failure in a hepatitis B virus endemic area

Liver transplantation for acute liver failure: are there thresholds not to be crossed?

Living Donor Liver Transplantation for Acute Liver Failure: Donor Safety and Recipient Outcome