Acute liver failure (ALF) is a complex, multisystemic, unpredictable, and rapidly progressing syndrome caused by numerous etiologies (viral infections, herbal medicine and drugs, autoimmune diseases, genetic and/or environmental factors). Although rare, it has a high death rate. This entity is potentially reversible and is characterized by rapid liver injury (<26 weeks), with the development of hepatic encephalopathy (HE) and coagulopathy (INR>1.5) in an individual with no pre-existing liver disease.1 The annual reported incidence is from 2,000 to 3,000 cases in the United States.2

The probability of spontaneous recovery or transplant-free survival (TFS) is related to etiology and HE grade. At present, the number of patients with TFS has increased, thanks to supportive medical management options, such as the use of N-acetylcysteine (NAC), continuous renal replacement therapy (CRRT), and less need for invasive mechanical ventilation.3–5 Nevertheless, the reported mortality rate ranges from 25 to 30% of patients that get on a liver transplantation waitlist. Nationally, transplant is considered an emergency procedure in patients that meet the criteria, and currently, one and 5-year post-transplant survival is 90 and 80%, respectively, with results becoming comparable to the population undergoing transplant for a chronic liver disease.6,7

A sudden decline in liver function, known as acute-on-chronic liver failure, is often misinterpreted in patients with chronic liver disease. Differentiating other conditions that are not part of the ALF spectrum, such as alcoholic hepatitis, sepsis, extensive liver resection, and liver trauma, is also vital for guaranteeing optimum and timely management.8

Distinguishing between ALF and acute decompensation of cirrhosis, or acute-on-chronic liver failure, can be difficult. Cirrhosis of the liver is highly prevalent worldwide and the development of decompensations (HE, variceal bleeding, and ascites) tends to appear at some point in the course of the disease, but determining the history of the chronic liver disease is easy the majority of the time. On the other hand, acute-on-chronic liver failure is characterized by intense systemic inflammation, a close temporal relation to a precipitating event, and the presence of one or multiple organ failures. The presentation of acute-on-chronic liver failure is sudden in a patient with decompensated cirrhosis of the liver and has a high short-term mortality rate (>20% at 28 days). It usually develops in the context of an added insult that causes a systemic inflammatory reaction. The causes can be intrahepatic (e.g., viral, drug-induced, alcohol-induced, etc.) or extrahepatic (e.g., hypoperfusion due to cardiac dysfunction, Budd-Chiari syndrome, etc.).9 It is vitally important to identify the differences between these entities because management changes radically. For example, ALF has a 1A status on the transplant waitlist, whereas acute-on-chronic liver failure is presently given no priority and the patient is placed on the list according to the MELD score.10

ALF is considered a relatively rare disease, with an annual incidence of 2,000 to 3,000 cases per year.1 It accounts for 4 to 5% of all liver transplants. Causes are diverse and vary according to region and socioeconomic level. In developed countries, paracetamol poisoning predominates in 45 to 55% of cases, with an incidence of 5.5 to 6.2 cases per million per year11 (Table 1). However, in developing countries, paracetamol overdose is less frequent and viral hepatitis (hepatitis A and E) and herbal medicines and other drugs play a fundamental role in the development of ALF.3,12,13 The etiology of the disease cannot be identified in 11 to 15% of adults and 50% of pediatric patients, with a possible 34% increase in developing countries,14 often due to lack of access to adequate laboratory testing.4,15,16 There is not much information on the epidemiology of ALF in Mexico. An increase in incidence and mortality attributable to viral causes of ALF have been seen in the country, but those observations are based on retrospective studies utilizing national registers, making them susceptible to information biases and variations in detection, depending on access to healthcare services.17

The course of the disease is variable and unpredictable. The mortality rate is 25 to 30% and the main causes of death are sepsis and cerebral edema.20 Despite not having clear statistics, the mortality rate can vary from 26.7 to 84% of cases in developing countries.15 On the other hand, spontaneous recovery can present in 45% of patients, depending on disease etiology.21

Different stages are distinguished within the spectrum of the clinical behavior of ALF. The first encompasses acute liver damage or acute liver injury (ALI), a term that refers to liver function test abnormalities,10 with no progression to HE. This condition can progress to ALF or be resolved with no sequelae.

Etiology plays a determining role in disease outcome. For example, spontaneous recovery and TFS, in cases of paracetamol-induced ALF, reach approximately 70%, whereas in hepatitis A virus infection, they reach only 56%, and in complications related to pregnancy, they reach 83%. In contrast, entities such as autoimmune hepatitis, drug-induced liver injury, acute hepatitis due to hepatitis B virus, and indeterminate causes show an unfavorable outcome, with the reported spontaneous recovery rate equal to or less than 35%.21,22

The definition of ALI is not uniformly established. In a prospective study that included 386 patients with the disease, defined according to its etiology (paracetamol-related: INR≥2 and ALT≥10 times the upper limit of normal; non-paracetamol-related: INR≥2, ALT≥10 times the upper limit of normal and bilirubin ≥ 3.0mg/dL), Koch et al. found that progression to an adverse outcome (ALF, death, or liver transplant) was associated with the etiology of ALI (non-paracetamol-related), bilirubin levels (>3mg/dL), INR (>1.7), serum paracetamol levels (>60mg/dL), and the duration of jaundice (>3 days).23

Transition to the ALF stage is characterized by the development of HE that is specified by cognitive decline (deficiencies in attention, reaction time, disorientation, inadequate behavior, somnolence, confusion, and unconsciousness) and neuromuscular function deterioration (bradykinesia, asterixis, dysarthria, ataxia, hyperactive deep tendon reflexes, nystagmus, etc.). Three causes with fulminant manifestations that could be associated with a pre-existing liver disease, such as Wilson’s disease, the reactivation of chronic infection due to hepatitis B virus, and autoimmune hepatitis, must be considered.16,23

The definition of ALF varies worldwide, but in the United States and Europe, the most accepted definition is that of a disease lasting < 26 weeks, in a patient with no pre-existing liver disease or cirrhosis, and associated with any grade of HE or coagulopathy (INR≥1.5).10

The length of time of disease progression provides information for associating etiology, complications, prognosis, and supportive medical treatment. In 1993, O’Grady et al.6 proposed one of the most accepted systems for describing disease progression and estimating its outcome. This classification is based on the time of the appearance of jaundice and the development of HE, subdivided into 3 groups: hyperacute < 7 days; acute 7-28 days; and subacute 4-12 weeks (Table 2).24 Even though this classification is the most widely used, it appears more logical to group acute and subacute into a single syndrome, because their speed of progression commonly overlaps, whereas patients with hyperacute liver failure have a distinct disease evolution and pattern.1

In addition to the O’Grady classification, there are others used worldwide for classifying ALF. An example is the classification proposed by Bernuau et al.25 in France in 1986, which distinguishes between fulminant liver failure (<2 weeks) and subfulminant liver failure (from 2 to 12 weeks). Another classification, presented in 1999 by Tandon et al.,26 under the auspices of the International Association for the Study of the Liver, defines ALF as acute if it develops in fewer than 4 weeks; its subdivisions are hyperacute (fewer than 10 days), fulminant (from 10 to 30 days), and subacute (from 5 to 24 weeks). On the other hand, in 2011 in Japan, Mochida et al.27 proposed a classification that distinguishes between acute (fewer than 10 days) and subacute (from 11 to 56 days) ALF.

Despite the variations in the time intervals and definitions, there is a general consensus that patients that experience a rapid development of HE from symptom onset, also show a greater probability of responding favorably to medical treatment.

Sudden and severe liver damage in ALF can have different causes, such as drug toxicity, viral infections, autoimmune disorders, genetic disorders, vascular problems, malignancies, and metabolic alterations (Table 3). To better comprehend the causes of ALF, we can classify them into 2 main categories: those triggered by paracetamol and those not related to paracetamol.

The comprehensive management of patients with liver failure is complex. It should include strict monitorization in an intensive care unit, a multidisciplinary approach involving intensivists, hepatologists, nephrologists, and infectologists. Medical support, focusing on ensuring hemodynamic stability and evaluating disease severity, is considered initial treatment, while at the same time carrying out a detailed analysis of the etiology. The most frequent and serious complications of ALF are related to neurologic, infectious, and hemodynamic alterations, and in the most severe cases, to the development of multiple organ failure (Fig. 1).

Figure 1.

Systemic complications in acute liver failure.

Created with Biorender.com

(0.54MB).

Metabolic alterations are frequent in ALF and energy expenditure is increased by 18 to 30%, compared with healthy individuals. Starting nutritional support, according to the status of the patient, is imperative, and the enteral route is the preferred first option. Support can be carried out orally in cooperative patients with low HE grades, or through an enteral catheter in cases of high HE grades and invasive mechanical ventilation. Increased protein support does not have an impact on HE progression, and so a dose of 1.0-1.5g/kg per day is recommended. Hypoglycemia, caused by the decrease in the liver glycogen stores should be actively monitored with glucometers every 1 to 2h. If present, support with continuous 10% dextrose infusion should be started for maintaining glycemia values between 150-180mg/dL. Lastly, fluid and electrolyte deficiencies (phosphorus, magnesium) should be monitored, and if present, replaced.10

Despite the advances in supportive medical management in patients with liver failure, high morbidity and mortality persists. Thus, treatment options are required that can be bridging therapies for those patients, spreserving liver function while they are on the transplant waitlist or when transplantation is not viable.

In such settings, a new supportive treatment modality has been proposed, which is high volume plasma exchange therapy (PLEX). The first randomized control study describing the usefulness of this therapy was reported in 2016 by Larsen et al.55 Their results showed that treatment with high-volume PLEX improved the in-hospital survival rate without liver transplantation, compared with standard medical therapy (59 vs 48%, respectively; p=0.0083). However, no difference in survival without liver transplant during hospitalization was observed (26 and 36%, respectively; p=0.17). Those authors reported a significant decrease in systemic inflammatory response and organ dysfunction markers in the group treated with PLEX. Subsequent studies have supported the idea that PLEX can have positive effects on the modulation of the inflammatory response, organ function, and the cerebral metabolic rate of oxygen in patients with ALF, which could lead to improved clinical results and a decrease in the morbidity and mortality associated with the condition.56,57 In general, there is information on the potential benefit of high-volume PLEX, but more studies are needed to better define its role in the management of ALF. Therefore, a generalized recommendation cannot be made at present.

ALF is the most serious of the liver diseases. The mortality rate with supportive medical treatment fluctuates around 60% and its clinical course tends to be insidious, sudden, and uncertain. Since the introduction of orthotopic liver transplantation (OLT) into the treatment algorithm, overall survival results have improved. Nevertheless, the main benefits of OLT in this group of patients are limited due to several factors. They include disease severity at the time of evaluation (irreversible brain damage or multiorgan failure), as well as the lack of organ availability at the precise moment.58

The goal of prognostic markers is to differentiate between patients with the probability of survival with only medical therapy (without the need for OLT) and patients with a poor prognosis in whom OLT should not be delayed. The main scales for determining disease severity are the King’s College Hospital criteria (KCC)59 and the Clichy-Villejuif criteria,60 among others.61

Currently, the majority of transplantation centers use the KCC (Table 7), which have 68-70% sensitivity and 82-92% specificity, as well as an 80% positive predictive value in paracetamol-related ALF and 70-90% for other etiologies.62

The prognostic score proposed by the Acute Liver Failure Study Group (ALFSG), the ALFSG index, includes HE grade, ALF etiology, vasopressor use, total bilirubin levels, and INR, and is a better predictor of TFS than the MELD or KCC scores.63 However, it must be pointed out that prospective validation of this model is still pending.

ALF that does not respond to supportive treatment is a clear indication for liver transplantation. It is currently the reason for approximately 4 to 8% of all transplants, according to that reported by the Scientific Registry of Transplant Recipients and the European Liver Transplant Registry.32,64

The transplantation decision should be made in a time lapse not over 3 days, through the evaluation of a multidisciplinary team, with the intention of preventing the clinical deterioration that would contraindicate a liver transplant.65 A comprehensive evaluation should include dynamic imaging of the liver and biliary tree and an echocardiogram, within the first 12 to 24h, to confirm the suitability of the patient for transplantation and evaluate the patient’s cardiopulmonary status. The candidates that meet the transplantation criteria are given priority on the waitlist, but if they have either significant clinical deterioration or notable improvement, their removal from the waitlist is considered.66

In 2020, the United Network for Organ Sharing adopted a new prioritization system for patients with ALF, categorizing them as having high short-term mortality and situating them in priority 1A (Table 8).67

In Mexico, the criteria proposed by the Centro Nacional de Trasplantes are the basis for enrolling a patient with ALF. They consist of a) no evidence of previous liver disease; b) patients in the intensive care unit with the following conditions: neurologic decline with any HE grade < 8 weeks of progression, INR ≥ 2, and need for renal replacement therapy; and c) can be supported by the KCC or Clichy-Villejuif criteria.

Patients registered on the liver transplant waitlist can be removed from it if they present with clinical improvement with spontaneous resolution or they have deterioration and a contraindication for transplant. The relevant contraindications to take into account can be classified into 3 main categories. First, medical contraindications and poor prognosis factors of active malignancy, HIV/AIDS infection, heart failure with reduced left ventricular ejection, dependence on ventilation support with an inspired fraction of oxygen greater than 90%, positive end-expiratory pressure, acute respiratory distress syndrome and concomitant acidosis, hemodynamic instability requiring the use of more than 2 vasopressors, uncontrolled sepsis, and confirmed invasive fungal infection; second, the presence of irreversible neurologic damage, such as encephalic herniation and severe intracranial bleeding; and lastly, the existence of psychosocial barriers, such as the lack of a support network and social support, uncontrolled substance abuse disorder, and a low probability of adherence to medical follow-up and pharmacologic treatment.67 The majority of these are classified as relative contraindications, with the exception of irreversible neurologic damage, which is an absolute contraindication.

Psychologic assessment and the evaluation of the social environment can be challenging due to the neurologic decline developed by patients, mainly in the presence of advanced HE. Inquiry into transplant acceptance, family support network, resources, and possible adherence to immunosuppressive treatment is important. ALF etiology, such as attempted suicide or intravenous drug use, can involve social stigmas, requiring accurate evaluations with respect to justice and equity.

Survival rates reported in Europe and the United States range from 79 to 84% in the first post-transplant year, 75% at 5 years, and 72% at 10 years. Male sex, donor age above 60 years, recipient age above 50 years, ABO incompatibility, and small graft size are factors that have been identified as predictors of mortality.32,61 The most frequent causes of death within that time period are infections (mainly fungal infections), neurologic complications, and multiple organ failure.68 In addition, patients that during their time on the waitlist required supportive measures (mechanical ventilation, vasopressor use, blood product transfusion, and a high number of medical and drug interventions due to neurologic complications) have worse survival.11,19

The timely detection of patients with ALD is essential, given that the start of early treatment and opportune referral to a transplantation center can significantly improve survival. ALF is a rare entity, whose main cause in developed countries is PP, whereas the principal causes in middle and low-income countries are acute hepatitis virus, especially hepatitis A virus and hepatitis E virus, and indeterminate etiologies. An increase in transplant-free survival in ALF, regardless of its presentation with or without acute kidney injury, has been observed through the use of CRRT. Optimizing supportive medical management in the areas of intensive care, carrying out continuous monitoring, and rapidly identifying complications of ALF, especially cerebral edema, infections, and coagulopathy, are all crucial. In the initial evaluation, prognostic transplantation-free survival scales should be utilized to identify patients that should begin to be evaluated for a liver transplant. In general, long-term survival results in patients that undergo liver transplantation due to ALF are favorable.

This article is based on a thorough bibliographic review, and so does not involve direct patient participation or the need for approval by an institutional ethics committee. Importantly, no identifiable personal data have been utilized and we have taken measures for protecting the privacy of any information that could have been used in the bibliographic review.

No financial support was received in relation to this article.

The authors declare that there is no conflict of interest.