Management of acute liver failure-an updated literature review

Abstract

Acute liver failure (ALF) is a rare but life-threatening condition marked by rapid hepatic dysfunction, coagulopathy and encephalopathy in patients without prior liver disease. Common causes include drug-induced liver injury, viral hepatitis, and metabolic or autoimmune disorders. This review provides an updated overview of ALF’s etiology, diagnosis, and management. Timely diagnosis and risk stratification using tools like the King’s College Criteria and Model for End-Stage Liver Disease score are critical for guiding care. Early identification of etiology allows targeted treatments, such as N-acetylcysteine for acetaminophen toxicity or antivirals for hepatitis. Supportive care in specialized intensive care units, focused on hemodynamics, cerebral edema prevention, and metabolic stabilization, remains the cornerstone of management. Advances in extracorporeal liver support systems, such as molecular adsorbent recirculating systems and plasma exchange, offer promising bridges to recovery or liver transplantation - the definitive treatment for irreversible liver injury. Expanded donor criteria and improved allocation policies have enhanced transplantation access. Despite progress, ALF carries significant morbidity and mortality. Emerging therapies, including stem cell treatments and immunomodulatory agents, show potential to revolutionize care. This review emphasizes the need for a multidisciplinary approach and continued research to improve outcomes and refine therapeutic strategies.

Key Words: Multidisciplinary management; Liver transplantation; Extracorporeal liver support; N-acetylcysteine; Model for End-Stage Liver Disease score; King’s College Criteria; Drug-induced liver injury; Coagulopathy; Hepatic encephalopathy; Acute liver failure

Core Tip: Acute liver failure (ALF) is a rapidly progressive and life-threatening condition that demands urgent recognition and intervention. This review highlights the latest insights into ALF’s diverse causes, diagnostic strategies, and management approaches. Emphasis is placed on early etiology identification, use of prognostic tools like King’s College Criteria and Model for End-Stage Liver Disease score, and timely initiation of targeted therapies. Advances in liver support systems and transplant accessibility have improved outcomes, yet ALF remains a critical challenge. A multidisciplinary, evidence-based approach is essential to optimize care and explore emerging treatments that may transform the future of ALF management.

INTRODUCTION

Acute liver failure (ALF) is a medical condition, initially described in 1970. Over time, its definition has evolved, and in the United States and Europe, it is now recognized as a potentially reversible but life-threatening disorder characterized by the rapid onset of liver dysfunction within 26 weeks[1]. ALF is defined as an acute episode of severe hepatic dysfunction with biochemical evidence of liver injury in patients without pre-existing chronic liver diseases, liver-induced coagulopathy not corrected by vitamin K supplementation, an international normalized ratio (INR) > 1.5 if the patient has encephalopathy or INR > 2.0 if the patient does not have encephalopathy[2]. The occurrence of ALF differs significantly across global regions. In developed nations, it is relatively rare, with an estimated annual incidence of 1 case to 6 cases per million individuals. In contrast, ALF is considerably more prevalent in developing countries, largely due to inadequate hepatitis virus vaccination coverage. As a result, outcomes are often worse in these areas because of limited access to adequate medical treatment[3].

A recent review of ALF epidemiology over the past five decades indicates a decreasing incidence of ALF due to hepatitis A and B, while cases linked to acetaminophen (APAP) have risen, particularly in the United States and Western Europe[4]. In the United States, ALF is estimated to affect around 2000 to 3000 individuals annually[1]. In both the United States and Europe, drug-induced liver injury (DILI) remains the leading cause of ALF, with APAP being the most commonly implicated drug[3]. On a global scale, up to 35% of ALF cases are considered to be of unknown origin, a figure likely influenced by limitations in diagnostic testing, undetected autoimmune hepatitis (AIH), or unidentified viral or drug-related causes[1,3,5].

Given the high mortality rate associated with ALF, identifying its underlying cause through patient history and appropriate investigations are crucial for initiating targeted therapies and improving patient outcomes[6]. The clinical challenges of ALF include hepatic encephalopathy (HE) and cerebral edema, sepsis, hypoglycemia, coagulopathy, renal impairment, and hemodynamic instability. The primary goal in managing ALF is to prevent and treat these complications, thereby allowing time for hepatic regeneration or facilitating liver transplantation (LT) when necessary[7]. This literature review aims to enhance understanding of ALF, enabling healthcare professionals to recognize early signs and symptoms, initiate timely management, and ultimately contribute to reducing its mortality rate.

ETIOLOGY AND RISK FACTORS

Understanding the various causes of ALF is crucial, as treatment depends on the underlying etiology. The most recognized causes are outlined below.

Drug induced liver injury

Drug induced liver injury (DILI) refers to liver damage caused by adverse reactions to medications, herbal supplements, or other chemical agents[8]. It represents the leading cause of ALF in Western countries, carrying a case fatality rate ranging from 10% to 50%[8]. The development of DILI involves a complex interplay of host-related, genetic, pharmacologic, and lifestyle factors that can influence a patient’s susceptibility, either through drug-specific mechanisms or independently[9]. Over 1000 medications and herbal products linked to DILI are listed in the NIDDK’s NIH LiverTox Database[10].

DILI can be classified into three main types based on the pattern of liver enzyme abnormalities: Hepatocellular, cholestatic, or mixed. When DILI occurs in a predictable, dose-dependent fashion - such as with APAP toxicity - it is referred to as intrinsic. In contrast, when liver injury arises unpredictably and is not clearly related to the drug dose or duration of therapy, it is termed idiosyncratic as shown on Table 1[8,11].

Table 1 Pathophysiology of acute liver failure.

Characteristic	DILI	Viral hepatitis	Autoimmune hepatitis	Ischemic hepatitis
Etiology	Drug dependent/intrinsic and drug independent/idiosyncratic	Hepatitis A, B, C, and E; less commonly CMV, HSV, EBV and VZV	Molecular mimicry; most common type 1 is associated with ANCA-abs and less common type 2 is associated with anti liver cytosol type 1 antibodies	Hypoperfusion to hepatic vasculature
Risk factors	Increased BMI, increased age, female sex, underlying liver disease (NAFLD), altered liver metabolism	Lack of access to clean water, unsanitary living conditions, IV drug use, risky sexual behaviors	Female sex, uncharacterized genetic predisposition	Most commonly associated with cardiac disease, respiratory failure and septic shock; severe burns, anaphylactic shock and thromboembolic event

DILI: Drug induced liver injury; BMI: Body mass index; NAFLD: Non alcoholic fatty liver disease; CMV: Cytomegalovirus; HSV: Herpes simplex virus; EBV: Epstein-Barr virus; VZV: Varicella-zoster virus; ANCA: Anti-neutrophilic cytoplasmic antibody.

While there are no definitive risk factors for developing DILI, certain pre-existing conditions may increase susceptibility. These include a high body mass index, advanced age, female sex, underlying liver diseases such as non-alcoholic fatty liver disease, and systemic conditions like diabetes mellitus[12-14]. Idiosyncratic DILI (I-DILI) is notably more common in women - accounting for about 59% of cases - possibly due to hormonal effects on immune modulation or differences in drug metabolism. On the other hand, individuals over the age of 50 appear to have an increased risk of DILI, which may be attributed to their more frequent use of prescription medications[12].

Genetic variations that affect liver metabolism and drug transport pathways likely contribute significantly to individual risk, although most allele-specific, drug-related associations require further validation before being applied in clinical settings[14]. While alcohol consumption is frequently regarded as a potential risk factor, no conclusive evidence supports its overall role in increasing the risk of DILI. Nonetheless, heavy alcohol use has been linked to an elevated risk of DILI in a drug-specific context, without a corresponding increase in mortality or the need for LT[15]. Anti-Tuberculosis drugs, particularly isoniazid, rifampin, and pyrazinamide, can cause DILI, occasionally leading to ALF. Risk factors include older age, preexisting liver disease, alcohol use, and malnutrition. Hepatotoxicity usually occurs within the first few weeks of treatment. Early recognition and prompt drug withdrawal are essential to prevent progression, and reintroduction should be done cautiously with close monitoring[16].

Viral hepatitis (hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus)

The majority of viral hepatitis cases are attributed to hepatotropic viruses - specifically hepatitis A, B, C, D, and E. However, non-hepatotropic viruses such as cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and varicella-zoster virus can also occasionally cause hepatitis[5]. According to the World Health Organization, there are an estimated 1.4 million new hepatitis A virus (HAV) infections globally each year. While most individuals recover completely, a small proportion develop ALF, with HAV responsible for about 3% of ALF cases[17] and approximately 0.5% resulting in hepatitis-related deaths[8]. HAV is primarily spread through the fecal-oral route, and key risk factors include limited access to clean water, inadequate sanitation, and sexual contact between men[18].

Hepatitis B virus (HBV) is the second most frequent cause of acute viral hepatitis. In the United States, more than 2000 cases of acute hepatitis B were reported in 2021, marking a significant decline from the approximately 25000 cases reported annually prior to the widespread adoption of hepatitis B vaccination programs[19]. Risk factors for HBV transmission include receiving blood transfusions, using intravenous drugs or sharing injection equipment, exposure to contaminated instruments during body piercing, engaging in sexual activity with an infected partner, and receiving organ transplants from HBV-positive donors[20].

Hepatitis C virus (HCV) is the most common cause of parenteral hepatitis globally, with a prevalence ranging from 0.5% to 2% of the population. Intravenous drug users and individuals with hemophilia are among the most affected groups. An estimated 71 million people worldwide are living with chronic HCV infection, contributing to nearly 400000 deaths annually. In the United States alone, around 50300 new HCV cases were reported in 2018, and approximately 2.4 million people are estimated to have chronic HCV infection[21]. Individuals diagnosed with acute hepatitis C are typically treated with the same antiviral medications used for chronic hepatitis C. Initiating treatment early can help reduce the risk of the infection progressing to a chronic state[18].

Hepatitis D virus (HDV), which requires the presence of HBV to replicate, has a poorly defined global prevalence but appears to have increased in recent years. Among HBV-infected individuals, intravenous drug users are at the highest risk for HDV infection[20]. HDV can lead to rapid liver failure or cirrhosis compared to just hepatitis B alone. Chronic hepatitis D often presents with advanced disease: 30% to 70% of patients have cirrhosis at diagnosis, and over 50% die from liver-related causes within 10 years. However, recent studies suggest that disease progression can vary, with over half potentially experiencing a milder course. Despite this, only 20% to 50% of cases are diagnosed, largely due to low awareness and limited access to accurate testing for HDV antibodies and RNA[21,22].

AIH

AIH is a rare, immune-mediated liver disease affecting fewer than 200000 individuals in the United States and under 1 in 2000 people in the European Union[23]. It is marked by the presence of autoantibodies, elevated gamma globulin levels, and characteristic histological features on liver biopsy[24]. AIH is classified into two types based on antibody profiles: Type 1 (AIH-1), associated with antinuclear and/or anti-smooth muscle antibodies, and type 2 (AIH-2), defined by anti-liver-kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies[23].

The condition primarily affects women and, while traditionally considered a disease of younger individuals, is now increasingly recognized in the elderly, often at advanced stages such as cirrhosis. The pathogenesis of AIH is believed to involve a combination of viral triggers - via molecular mimicry that causes immune responses to attack liver cells - and genetic susceptibility, particularly involving certain human leukocyte antigen alleles. However, genetic predisposition alone appears insufficient to cause the disease[23-25]. Although AIH typically presents as a chronic necro-inflammatory liver disease, up to a quarter of patients may present acutely, and a small fraction may develop autoimmune ALF. Early diagnosis is essential, as prompt initiation of corticosteroid therapy often leads to a dramatic clinical response. If left untreated, AIH can progress to cirrhosis, liver failure, and potentially death, or necessitate LT[26].

Ischemic and shock liver

Ischemic hepatitis - also known as hypoxic hepatitis or shock liver - is a diffuse liver injury resulting from a sudden and severe decrease in hepatic blood flow. It is marked by centrilobular hepatocellular necrosis and is most often associated with conditions like cardiac dysfunction, respiratory failure, or septic shock. In critically ill patients, its occurrence is associated with a poor prognosis, with a reported prevalence of 2.4%-11% in intensive care unit (ICU) settings[27-29]. The diagnosis is based on three main criteria: The presence of a clinical setting like heart, circulatory, or respiratory failure; a sudden and significant yet temporary spike in aminotransferase levels; and exclusion of other causes, such as viral or drug-induced hepatitis[30].

Hypoxic hepatitis predominantly affects elderly men with underlying conditions such as heart failure or chronic respiratory disease. Clinical signs may include right upper quadrant pain, hepatomegaly, and elevated bilirubin levels, with possible complications like encephalopathy - typically due to the primary illness rather than liver damage. Both hypoglycemia and hyperglycemia can be present. Management focuses on promptly addressing the underlying cause through circulatory support, blood pressure stabilization, and improving hepatic oxygenation using inotropes, vasodilators, and diuretics, as delayed treatment increases mortality risk[31-33].

Dengue virus

Dengue virus infection, common in tropical regions, can cause liver involvement ranging from mild enzyme elevation to severe ALF, particularly in Southeast Asia. Despite its significant impact, dengue-related acute liver failure (DALF) is understudied. A review of literature up to December 2023 showed that DALF mainly affects pediatric patients (1.1%-15.8%) with increasing incidence, especially in India. Among pediatric ALF cases, dengue accounted for 6.7%-34.3%. Risk factors for DALF include age ≤ 40, persistent nausea/vomiting, elevated bilirubin, alkaline phosphatas, aspartate aminotransferase > 1000 IU/mL, atypical lymphocytes > 10%, low platelets, severe hepatitis, and Model for End-Stage Liver Disease (MELD) > 15. Histology often reveals multilobular necrosis and steatosis. Mortality ranges from 0% to 80%, with low admission pH, high lactate, and cirrhosis predicting worse outcomes. N-acetyl cysteine (NAC) has shown mixed results; evidence on extracorporeal support is limited, and liver transplant criteria are not well established Figure 1[34].

Figure 1 Pathophysiology of liver failure. DAMP: Damage - associated molecular pattern; PAMP: Pathogen - associated molecular pattern; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor alpha; IL: Interleukin.

Risk factors

Increased body mass index, increased age, female sex, underlying liver disease (non alcohol associated fatty liver disease), altered liver metabolism. Lack of access to clean water, unsanitary living conditions, IV drug use, risky sexual behaviors. Female sex, uncharacterized genetic predisposition. Most commonly associated with cardiac disease, respiratory failure and septic shock; severe burns, anaphylactic shock and thromboembolic event.

PATHOPHYSIOLOGY

The pathogenesis of ALF involves complex interactions between hepatocyte injury, oxidative stress, inflammation, and systemic derangements, ultimately leading to multi-organ failure. Key mechanisms include hepatocyte necrosis, oxidative and inflammatory damage, disseminated intravascular coagulation (DIC), and cerebral edema.

Hepatocyte death in ALF arises from various hepatotoxic insults, including viral infections (e.g., hepatitis), drug-induced injury (notably APAP toxicity), ischemia-reperfusion injury, and metabolic dysfunction, all of which lead to oxidative stress[35]. The primary mechanisms of hepatocyte death - apoptosis, necrosis, and necroptosis - are heavily influenced by mitochondrial dysfunction[36], where excessive reactive oxygen species (ROS) drive mitochondrial permeability transition, cytochrome c release, and caspase activation, promoting apoptosis. Concurrent activation of c-Jun N-terminal kinase exacerbates mitochondrial damage, resulting in necrosis and the release of damage-associated molecular patterns (DAMPs) that amplify the inflammatory response, further perpetuating hepatic injury. Oxidative stress leads to lipid peroxidation, protein oxidation, and DNA fragmentation, causing mitochondrial dysfunction and adenosine triphosphate depletion, which increases hepatocyte vulnerability[37]. Inflammation is further exacerbated by the recruitment of neutrophils and macrophages that release pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin (IL)-1β, and IL-6, activating Kupffer cells and creating a feedback loop that amplifies cellular damage. This cascade often triggers the systemic inflammatory response syndrome (SIRS), resulting in endothelial dysfunction, increased vascular permeability, and multi-organ failure[38-40].

The liver’s role in hemostasis is compromised in ALF due to the loss of synthetic function, resulting in a consumptive coagulopathy. This is marked by elevated INR, thrombocytopenia, and hypofibrinogenemia, predisposing patients to bleeding. Simultaneously, systemic inflammation and endothelial dysfunction contribute to a prothrombotic state, leading to DIC. Activation of tissue factor and the coagulation cascade, coupled with impaired fibrinolysis due to increased plasminogen activator inhibitor-1, promotes microvascular thrombosis, worsening hepatic ischemia and multi-organ dysfunction[38].

HE in ALF results from the accumulation of neurotoxic metabolites, primarily ammonia, which crosses the blood-brain barrier and induces astrocyte swelling. Ammonia is normally metabolized in the liver through the urea cycle, but in ALF, its accumulation leads to increased glutamine levels in astrocytes, causing osmotic imbalance and cellular edema. This contributes to cerebral edema, increased intracranial pressure (ICP), and the risk of transtentorial herniation. Additionally, systemic inflammation exacerbates neuroinflammation by activating microglia and increasing blood-brain barrier permeability, worsening neurological dysfunction[41-43]. Understanding the pathophysiological mechanisms driving the most severe complications of ALF is critical to anticipating disease progression and guiding timely, targeted management.

CLINICAL PRESENTATION AND DIAGNOSIS

Early symptoms and progression

ALF often begins with nonspecific symptoms, making early detection challenging. Patients may initially report fatigue and loss of appetite. As the condition progresses, symptoms can range in severity and may include jaundice, abdominal pain, and a tendency to bleed due to impaired blood clotting[44]. Neurological changes - such as subtle shifts in mood, behavior, or cognition - are often early indicators of declining liver function. These neuropsychiatric signs can escalate quickly, potentially developing into severe HE characterized by confusion, agitation, or coma[45]. The rapid progression of symptoms is a key feature that distinguishes ALF from chronic liver disease and has important implications for clinical management[46].

Laboratory and biomarker assessment

Prompt laboratory evaluations are essential in diagnosing and monitoring ALF. A thorough liver function test panel can indicate elevated transaminases (aspartate aminotransferase and alanine aminotransferase) which typically reflect hepatocellular damage. On the other hand, total bilirubin indicates the liver’s ability to process waste products[47]. In addition, assessment of the liver’s synthetic function, including prothrombin time and INR, can reveal significant coagulopathy which in its turn serves as one of the hallmark signs of acute hepatic injury[48]. Serum ammonia levels are frequently used to gauge the risk of HE. Although elevated ammonia correlates with encephalopathy, clinical judgment remains vital because the correlation is not always absolute[49]. Additionally, further tests including viral hepatitis panels, toxicology screens, and autoimmune markers may help identify the underlying cause of ALF as well as ensuring adequate control of culprit triggers.

Imaging studies and liver biopsy

Diagnostic imaging of liver failure often begins with Doppler ultrasound, which helps rule out vascular disorders including Budd Chiari syndrome that can present similarly to ALF. This noninvasive test can also provide insight into the blood flow dynamics within the hepatic vessels[50]. If the initial ultrasound is inconclusive, computed tomography or magnetic resonance imaging can be used to detect subtler lesions or masses that may contribute to liver dysfunction. Although liver biopsy remains a diagnostic option, clinicians must balance the potential benefits of identifying specific pathologies (such as AIH, Wilson’s disease, or malignancy) against the risks, particularly bleeding, in patients who already have compromised coagulation[51]. For individuals with profound coagulopathy, a transjugular liver biopsy might be considered as a safer alternative to a percutaneous approach[52].

Prognostic scoring systems

Once ALF is suspected or confirmed, prognostic scoring systems play an essential role in guiding treatment decisions, including the urgency of listing a patient for LT. One of the most established tools is the King’s College Criteria (KCC), which uses factors like etiology of liver failure, prothrombin time/INR, and grade of encephalopathy to predict outcomes and further evaluation of emergent transplant[45]. Although specific parameters differ depending on whether ALF is APAP-induced or caused by other etiologies, the fundamental principle remains the same. For instance, the presence of severe metabolic acidosis, profound coagulopathy, and/or advanced encephalopathy indicates a high mortality risk. Notably, an arterial pH below 7.3 irrespective of encephalopathy, or a combination of advanced encephalopathy with a significantly prolonged prothrombin time (prothrombin time > 100 seconds) and elevated creatinine levels, justifies immediate consideration for transplant in the setting of APAP induced ALF[53]. Similarly, a prothrombin time exceeding 100 seconds or simultaneous presence of jaundice persisting over seven days before encephalopathy or elevated bilirubin in the setting of non-APAP induced ALF can indicate a poor prognosis. Additional scoring tools include the MELD score, originally developed for chronic liver disorder but it is also adapted to acute settings. Over time, MELD has become an integral part of organ allocation systems for chronic liver failure. Despite its chronic disease focus, several components of MELD - namely bilirubin, creatinine, and INR - are still highly relevant to ALF because they reflect both hepatic synthetic dysfunction as well as renal impairment. It can help clinicians gauge the urgency of treatment and potential transplant needs in acute settings. Nevertheless, it is vital to remember that MELD was never specifically designed for ALF, so its prognostic accuracy can be lower than that of more specialized criteria such as the KCC. In practice, both scoring systems complement clinical judgment: They can guide the decision to pursue emergent transplantation and prompt timely referral to specialized centers. Given the potential for abrupt deterioration in ALF, re-evaluating these scores frequently is key to tracking disease progression and intervening before irreversible damage occurs[53].

MANAGEMENT STRATEGIES

Managing ALF primarily involves providing life support, identifying the underlying cause for specific treatment, and preventing potential complications. Pinpointing the etiology is crucial for effective, targeted therapy. It is also advisable for these patients to be treated in specialized centers equipped for LT, which often becomes the ultimate treatment option in some instances[5].

Supportive care in the ICU

Due to the rapid progression, severity, and multi-organ involvement in ALF, individuals presenting with signs such as encephalopathy, acute kidney injury (AKI), low blood pressure, elevated lactic acid levels, or low blood sugar should be promptly admitted to the ICU, as they are at increased risk of rapid clinical decline[54]. In the ICU, the management of liver failure is primarily supportive with specific considerations that will be described in this section.

As with all critically ill patients, maintaining airway protection and hemodynamic stability is crucial to improving clinical outcomes. In terms of airway and respiratory management, spontaneous hyperventilation - commonly seen in ALF as a compensatory response - should be allowed. When intubation is necessary, particularly in cases of severe encephalopathy (grade III or IV) for airway protection, this pattern of breathing should neither be actively suppressed nor routinely mimicked. Anaesthetic induction strategies should aim to minimize elevations in ICP. Additionally, lung-protective ventilation should be employed, with targeting tidal volumes of 6-8 mL/kg, while maintaining partial pressure of arterial oxygen (PO₂) between 10-12 kPa and partial pressure of carbon dioxide (pCO₂) between 4.5-5.5 kPa to support neuroprotection[54,55].

Similar to what is observed in SIRS or sepsis, patients with ALF often exhibit significantly reduced systemic vascular resistance, leading to vasodilatory shock accompanied by a high cardiac output state. Consequently, fluid resuscitation and restoration of adequate organ perfusion are central components of ALF management. The recommended target for mean arterial pressure is above 65 mmHg, with a higher threshold of approximately 80 mmHg in cases of elevated ICP or in patients with uncontrolled chronic hypertension. Balanced crystalloid solutions are preferred for volume replacement, alongside careful monitoring of acid–base status, plasma electrolytes, and cardiac output[5,54-56].

AKI develops in approximately 70% of patients with acute liver ALF. Contributing risk factors include hypotension, sepsis or SIRS, advanced age, and APAP-induced ALF. Continuous renal replacement therapy (RRT) is required in around 30% of cases and is preferred over intermittent hemodialysis, as it reduces the metabolic and hemodynamic fluctuations associated with intermittent dialysis. This is especially critical when ammonia levels exceed 150 μg/dL, to help mitigate the risk of cerebral herniation[3,57]. Based on the high incidence of AKI in patients with ALF, starch-based solutions should be avoided. Conversely, albumin may be considered for volume resuscitation; while it does not confer a survival benefit, it can improve hemodynamic stability and serve effectively as a colloid volume expander[56].

When patients do not respond adequately to fluid resuscitation, vasopressor therapy should be initiated. Norepinephrine is the first-line agent of choice. If hypotension persists, vasopressin can be added. In cases of refractory hypotension, corticosteroids may be considered due to the recognized association between ALF and relative adrenal insufficiency. However, steroid use should be carefully individualized, taking into account the underlying etiology of liver injury and the potential risk of infection[3].

In patients with ALF, close monitoring for signs and symptoms of active bleeding is essential, as platelet dysfunction is common in this population. Blood product transfusions should be reserved for cases of active bleeding or prior to invasive procedures. Prophylactic use of proton pump inhibitors is recommended to reduce the risk of gastrointestinal bleeding. Infection surveillance is also critical - timely collection of cultures and initiation of empiric antibiotic therapy when indicated are key components of care. Nutritional support should not be overlooked; patients should receive 1.0 g to 1.5 g of protein per kilogram of body weight per day. Additionally, blood glucose levels must be closely monitored, with target ranges between 160 mg/dL and 200 mg/dL[5].

Specific treatments based on etiology

As mentioned earlier, determining the underlying etiology of acute ALF is essential for guiding individualized treatment strategies and improving patient outcomes. In cases of APAP-induced ALF, management focuses on limiting further drug absorption and facilitating its removal from the gastrointestinal tract. Activated charcoal is one therapeutic option, but it is only effective if administered within four hours of APAP ingestion. Its use is contraindicated in patients with an unprotected airway or those with gastrointestinal compromise. Potential side effects include aspiration pneumonia, diarrhea, constipation, ileus, and vomiting[58]. NAC should be administered early in patients with APAP-induced ALF after 4-8 hours of ingestion. By supplying cysteine, a precursor to glutathione, NAC helps neutralize N-acetyl-p-benzoquinone imine - the toxic metabolite responsible for hepatocellular injury[56].

Supportive care remains the mainstay of treatment for patients with ALF due to hepatitis A or E, as no specific antiviral therapies are currently available. In contrast, patients with acute or reactivated hepatitis B should be treated with nucleoside or nucleotide analogs. For ALF caused by herpes simplex virus or varicella zoster virus, intravenous acyclovir at a dose of 5 mg/kg to 10 mg/kg every 8 hours is recommended. Cytomegalovirus-related ALF should be managed with intravenous ganciclovir at 5 mg/kg every 12 hours. In cases where AIH is suspected, intravenous methylprednisolone at a dose of 60 mg/day may provide benefit[59,60].

Role of plasma exchange and extracorporeal liver support devices

Effective strategies are essential to sustain the patient’s condition until either spontaneous liver recovery occurs or a suitable donor organ becomes available for transplantation. Among the various artificial liver support systems, therapeutic plasma exchange (TPE) has shown to improve survival in patients with ALF[34]. While other artificial liver support systems show promise - particularly as a bridge to transplantation - TPE stands out due to its unique mechanism: It removes the entire plasma, including harmful DAMPs, and replaces it with donor fresh frozen plasma[61].

TPE has demonstrated the ability to lower inflammatory cytokine levels, regulate adaptive immune responses - potentially decreasing infection risk - and effectively remove both albumin-bound and water-soluble toxins in liver failure[59]. In cases of ALF, high-volume TPE has been particularly beneficial, reducing the need for vasopressors and improving survival outcomes, especially among patients who are not candidates for LT[62,63]. On the other hand, extracorporeal liver support (ECLS) is a therapeutic modality designed to replicate key liver functions by filtering and detoxifying blood through an external device. It is primarily used as a bridge to LT and has been associated with a significant reduction in mortality among patients with ALF. In some cases, ECLS can help reverse severe complications such as HE and multi-organ failure, potentially allowing for spontaneous recovery of liver function without the need for transplantation[64].

Extracorporeal liver support devices are broadly divided into two categories based on their function: Artificial systems, which focus solely on blood detoxification, and bio-artificial systems, which incorporate hepatocytes to mimic metabolic liver functions[65]. The Albumin Dialysis Systems works by circulating the patient’s blood through an albumin-impermeable membrane, where toxins transfer to an external 20% human albumin solution based on concentration gradients. This albumin is then purified using charcoal and anion exchange columns before recirculation. Each treatment session typically lasts 6-8 hours with a blood flow rate of 150-250 mL/minutes[65,66].

Common side effects of Albumin Dialysis Systems include hypotension and clotting of the extracorporeal circuit, though bleeding risks are not significantly elevated compared to standard medical therapy. Anticoagulation with heparin or citrate is generally recommended[65,67]. The other modality is Single-Pass Albumin Dialysis, a simpler modality that mimics molecular adsorbents recirculating system but without recycling the albumin. Single-Pass Albumin Dialysis uses a single pass of an albumin-rich solution to dialyze blood and can be carried out using standard RRT machines, making it more accessible. However, it requires continuous use of fresh albumin, increasing cost and resource use[65,68].

Indications for LT

LT is a critical, life-saving option for individuals with ALF. Despite notable improvements in outcomes with medical treatment, less than 50% of patients survive without a transplant[69]. Given the growing number of patients awaiting LT and the ongoing scarcity of donor organs, careful selection of transplant candidates and efficient use of available organs are essential to optimize outcomes and avoid unnecessary graft loss. Various scoring systems have been developed to help identify patients who are most likely to benefit from transplantation and who should be promptly referred to specialized liver centers[70].

There are three fundamental principles guiding the selection of patients for LT. First, the individual must have a form of liver failure that is irreversible and likely to be fatal without a transplant. Second, the patient must possess adequate physiological reserve to tolerate the surgery and the immediate recovery period. Third, transplantation should offer a meaningful improvement in both survival and overall quality of life[71].

Patients with ALF should be referred to specialized liver units when they exhibit signs of severe disease, such as an INR greater than 3.0 or a prothrombin time over 50 seconds, worsening HE, persistent hyperlactatemia or hypotension despite resuscitation efforts, metabolic acidosis with a pH below 7.35, AKI, bilirubin levels exceeding 17.5 mg/dL, or evidence of a shrinking liver on imaging. These indicators reflect a critical deterioration and highlight the need for advanced management and potential LT[70,72].

COMPLICATIONS AND PROGNOSIS

Multiorgan dysfunction and sepsis

Immunological dysfunction in ALF: ALF is associated with a biphasic immune response. Initially, there is systemic hyperactivation, followed by sustained immunosuppression. This reversal increases vulnerability to secondary infections, most commonly respiratory, biliary, and pleuroperitoneal infections[73].

Hemodynamic alterations: The hemodynamic profile of ALF mirrors septic shock, with hyperdynamic circulation, decreased systemic vascular resistance, and reduced effective circulating volume. This condition may begin with hypovolemia, especially in those with reduced consciousness, progressing to systemic vasodilation due to the SIRS phenomenon and cytokine storm. These changes lead to end-organ hypoperfusion, lactic acidosis, and ultimately renal failure[1,59].

Early activation of the innate immune system: Viral hepatitis induces an immune response primarily triggered by pathogen-associated molecular patterns, with necrotic hepatocytes release DAMPs such as histones, extracellular DNA, and high mobility group box-1, which initiate the immune response in toxin-induced injury. Immature dendritic cells, macrophages, natural killer cells, and monocytes secrete proinflammatory cytokines (e.g., tumor necrosis factor α, IL-1β, IL-6) and ROS, inducing systemic inflammation[74,75].

Late-stage immunosuppression: As ALF progresses, a compensatory anti-inflammatory response mediated by IL-4, IL-10, and tumor growth factor -beta leads to immunosuppression, increasing susceptibility to infections. Elevated IL-10 inhibits monocyte function, and decreased liver synthetic capacity results in diminished complement production, impairing neutrophil-mediated defense against encapsulated bacteria. Functional neutrophil impairment includes decreased ROS production, reduced pathogen engulfment, and lower complement receptor expression. Additionally, reduced plasma fibronectin impairs Kupffer cell-mediated pathogen clearance[74]. These immune deficiencies are worsened by the use of invasive medical devices, increasing the risk of nosocomial bacterial and fungal infections. While prophylactic antibiotics are not universally recommended, surveillance cultures every 48 hours and prompt antimicrobial therapy are advised[59,73].

Septic shock and mortality: Sepsis remains the leading cause of mortality in ICUs, affecting an estimated 18 million people globally each year, with a mortality rate of 28%-40%. The liver’s central role in metabolism, synthesis, and immune regulation can hinder the host’s ability to modulate immune responses effectively, increasing susceptibility to both inadequate pathogen clearance and immune-mediated tissue damage[76-78]. The exact mechanisms behind sepsis-induced liver injury remain unclear. However, current research suggests that a combination of factors - including dysregulated systemic inflammation, microbial translocation, microcirculatory disturbances, hepatocyte death, metabolic dysfunction, and intrahepatic inflammation - contribute to liver damage in the setting of sepsis[79]. During sepsis, the liver is essential for immune defense and metabolic regulation, but excessive inflammation can cause sepsis-induced liver injury. This condition significantly worsens outcomes, with associated mortality rates between 54% and 68%[80].

Clinical implications: The shift from SIRS to compensatory anti-inflammatory response syndrome shapes the disease course. This dysregulation of the immune cascade accounts for the loss of vascular tone, refractory hypotension, impaired tissue oxygenation, and lactic acidosis, leading to multiorgan failure (cardiovascular collapse, cerebral edema, AKI, respiratory failure, sepsis, etc.), which are major predictors of mortality in ALF[59,74].

Coagulopathy and bleeding risk

Patients with ALF frequently present with elevated INR and thrombocytopenia, suggesting bleeding risk. However, clinically significant spontaneous bleeding is uncommon (about 7%-10%) and rarely a direct cause of death[1,75,81]. Thrombotic events occur at similar rates, challenging the traditional view of ALF as a purely hypercoagulable state[78]. While INR is useful prognostically, it does not reliably predict bleeding risk. Thrombocytopenia, in contrast, correlates more strongly with both bleeding and poor outcomes.

Emerging evidence supports a state of rebalanced hemostasis in ALF. Simultaneous decline in pro- and anticoagulant liver-derived factors, elevated von Willebrand factor, and reduced A disentegrin and metalloprotinease with thrombospondin type 1 motif, member activity create a delicate equilibrium. This imbalance promotes endothelial activation and contributes to disease progression[1]. When bleeding does occur, it's typically mild and arises from upper GI stress ulcers due to SIRS, and only about 15% of cases require transfusions[1,75]. Intracranial hemorrhage, though rare, can be fatal due to mass effect[75].

Data from the ALFSG registry (n = 1800) showed bleeding directly caused death in only 2% of cases, underscoring its minor role in overall mortality[75]. Despite impaired coagulation factor production, thrombin generation and fibrinolysis often remain intact. Studies show no significant differences in thrombin potential or clot lysis time between bleeders and non-bleeders. Instead, von Willebrand factor/A disentegrin and metalloprotinease with thrombospondin type 1 motif, member imbalance - especially in the setting of multiorgan failure - is associated with worse outcomes and increased susceptibility to both bleeding and thrombosis.

This imbalance may promote intrahepatic microthrombi formation due to platelet aggregation in hepatic microvasculature, accelerating liver failure[81]. DIC occurs in about 38% of ALF patients, with Japanese Association for Acute Medicinescores ≥ 4 correlating with thrombocytopenia but not directly with bleeding[79]. Notably, INR does not correlate with bleeding, whereas platelet-dependent Rotational Thromboelastometry parameters (e.g., clot firmness) better reflect bleeding risk and offer a more holistic view of coagulation in ALF[75].

AKI

AKI occurs in 40%-80% of ALF cases in Western countries[81,82]. Mechanisms include acute tubular necrosis from hypovolemia, nephrotoxicity (e.g., APAP metabolites), or functional renal failure resembling hepatorenal syndrome[81-84]. AKI worsens prognosis in all etiologies, especially in APAP induced ALF, with 30% requiring RRT[85,86]. Persistent AKI, seen in 56.1% of patients, reduces transplant-free survival (adjusted odds ratio = 0.62)[85].

Long-term outcomes and recovery prospects

Mortality and long-term outcomes in ALF depend heavily on etiology, clinical presentation, and access to LT[1,59]. Over the past three decades, improved clinical care—including advancements in intensive care, timely intravenous NAC administration, and expanded access to LT - has led to improved survival in ALF, with some etiologies now showing excellent transplant-free survival[1,57,87].

APAP hepatotoxicity has one of the best prognosis, especially when treated early with NAC[1,56]. Mortality rates are approximately 28%, with up to a third requiring LT, though most recover with supportive care alone. Moderate alcohol consumption (≥ 3 drinks/week) worsens APAP-ALF outcomes, with higher peak AST (8000 vs 5279 IU/L), bilirubin (5.0 vs 3.6 mg/dL), and creatinine (2.2 vs 1.5 mg/dL)[88].

In contrast, I-DILI has a less predictable course. Three-week transplant-free survival ranges from 23.5% to 38.7%, with overall survival around 66%[1]. Complementary and alternative medicine-related ALF, a subgroup of I-DILI, carries poorer outcomes due to delayed presentation and higher transplant rates[1,56]. In Western countries, non-APAP ALF is often due to anti-tubercular drugs (30%), while in Asia, traditional Chinese herbs are more commonly implicated[86].

Viral hepatitis-related ALF outcomes vary by virus. HAV-related ALF has a relatively good prognosis with 70% transplant-free survival, though ALF is rare in HAV. HBV -related ALF is more fulminant, with nearly three-quarters of patients dying or requiring LT[1,81]. Hepatitis E virus is highly fatal among pregnant women, with mortality between 51%-75%[84]. Herpes simplex virus-related ALF is rare and associated with poor outcomes, even with antiviral therapy[1]. Though rare (0.7%), dengue-induced severe hepatitis can progress to ALF with high mortality; the MELD score best predicts outcome in these cases[89].

Toxin-mediated ALF, such as from Amanita mushroom poisoning, may have good outcomes if recognized early and treated with silibinin or penicillin G; most survive without LT. In severe cases, LT has excellent results[1]. Wilson disease-related ALF has a poor prognosis, with limited response to medical therapy. The revised Wilson Index (≥ 11) and Nazer Index (≥ 7) predict high mortality[90]. AIH-related ALF also has a poor prognosis, with mortality between 16–19% and nearly half requiring LT despite corticosteroid therapy. Post-transplant outcomes are excellent, although recurrence rates range from 30%-80% if immunosuppression is withdrawn[1,91].

Pregnancy-related ALF, including acute fatty liver of pregnancy and Hemolytic anemia, elevated liver enzymes and low platelet count syndrome, generally resolves after delivery. Within 21 days, 69% of patients recover spontaneously, 14% undergo LT, and 11% die[1,59]. Timely obstetric intervention is essential. Budd-Chiari syndrome outcomes have improved significantly with anticoagulation, transjugular intrahepatic portosystemic shunt, and LT, with 1-, 3-, and 5-year survival rates of 76%, 71%, and 68%, respectively. Ischemic liver injury, often due to shock, typically resolves with correction of the hemodynamic insult, and rarely requires LT. Conversely, malignant hepatic infiltration has a grim prognosis - transplant is not feasible and 85% die within three weeks. Indeterminate ALF, where no etiology is found, has a poor prognosis, with low spontaneous recovery rates and frequent need for LT.

Overall, long-term outcomes after LT in ALF are promising. One-year survival is about 80%, and five-year survival is about 75%[1]. Most post-transplant deaths occur in the early postoperative period due to infections, neurologic worsening, or multiorgan failure. Long-term survival is excellent in those who survive the early period. Predictors of post-transplant mortality include elevated serum creatinine, need for life support during transfer, male sex, obesity, ABO incompatibility, and small graft volume. Living donor LT, although less common, offers outcomes comparable to deceased donor LT[59].

ALF survivors - whether via spontaneous recovery or LT - commonly experience persistent neurocognitive dysfunction, psychiatric symptoms (e.g., anxiety, depression), chronic fatigue, and post-intensive care syndrome[59]. In APAP-related ALF, liver regeneration is robust, and full recovery of hepatic function is common. Early biomarkers like miR-150 and miR-27a may improve prognostication beyond standard clinical scoring[87]. Predicting ALF outcomes likely depends on dynamic biomarkers of cell death, regeneration, and inflammation, integrated with clinical models like KCC, MELD, or acute liver failure study group prognostic index. Large-scale studies using proteomic, transcriptomic, and genomic tools will be key to refining long-term prognosis[75]. A study evaluated whether early changes in clinical variables can better predict outcomes in ALF than traditional static models. Using data from 380 ALF patients, researchers developed the ALF Early Dynamic model, incorporating four variables over 3 days: Arterial ammonia, serum bilirubin, INR, and encephalopathy > grade II. The model showed excellent predictive accuracy (area under the curve: 0.91-0.92) and outperformed existing models like the KCC criteria and MELD score. An ALF Early Dynamic score ≥ 4 was strongly predictive of mortality. The model may enhance clinical decision-making in ALF[92].

FUTURE DIRECTIONS AND EMERGING THERAPIES

Although outcomes for liver failure have improved over the last two decades, it remains a condition with high risk of mortality. Early detection of liver failure can dramatically help improve outcomes. Vasopressor support and high grade HE are two factors that greatly increase the need for LT[93]. Among patients with ALF, those with autoimmune causes, I-DILI, or indeterminate etiologies tend to have the poorest outcomes without transplantation[93].

A few limitations to obtaining a liver transplant include the wait list for transplantation as well as the survivability of the recipient until a suitable donor graft is obtained[64]. Primary hepatocytes, induced pluripotent stem cells, embryonic stem cells, as well as mesenchymal stem cells (MSCs) can be used for recellularization of the liver[93]. Hepatocyte-like cells (HLC) which have been generated by reprogramming somatic cells have been transplanted into patients and studied. The transplanted HLCs therapeutic efficacy in mice with chronic liver disease and treatment of metabolic liver disease has shown progress[89]. Due to progress in animal models, studies for the clinical applications of HLCs are anticipated in the near future[94]. Advancements in gene therapy have also aimed to address genetic causes of liver injury. Hepatocytes can be targeted with gene therapy by repair of a genetic mutation to correct the protein, addition of genetic material to express a missing protein, and gene silencing to eliminate a protein or reduce accumulated toxic metabolites that cause liver injury[93]. However, the use of gene therapy in clinical trials has not had the desired effect including the development of leukemia in a patient and causing death in another. Neurotoxicity, tumorigenicity and hepatotoxicity are also severe adverse effects that could occur due to gene therapy.

Compared to LT, hepatocyte transplantation offers several advantages - it is less invasive, easier to perform, allows for the use of cells from a single donor for multiple recipients, and permits cryopreservation of hepatocytes after genetic manipulation[94]. Hepatocyte transplant has been shown to provide hepatic function in patients with ALF[94]. Advances in hepatocyte transplantation include in vitro primary human hepatocyte (PHH) and preparative hepatic irradiation in combination with mitogenic stimuli which have the ability to efficiently repopulate the liver.

With PHH, hepatocytes can be dedifferentiated into hepatic progenitor-like cells which would result in quality assured cells for hepatocyte transplantation. The drawback of PHH is that cryoprecipitation negatively affects the viability of PHH. In order to combat this, recent studies have been done to encapsulate hepatocytes before cryopreservation and to add membrane stabilizers and antioxidative chemicals. Strategies to prevent the immune rejection of hepatocyte transplantation are currently being studied. Hepatocytes, which are known to carry CD40 (a marker of T cell activation associated with graft rejection) can be incubated with anti-CD40 antibodies to reduce immune response[65,94]. Despite limited advances in ALF treatment, MSCs have emerged as a promising therapeutic option due to their availability, low immunogenicity, and lack of ethical concerns. While MSCs show potential in ALF therapy, further research is needed to optimize their use. This review explores the mechanisms of MSC action in ALF, strategies to enhance their effectiveness, and approaches for improving MSC transplantation[95].

CONCLUSION

ALF is a complex, rapidly evolving condition that requires prompt recognition, accurate prognostication, and targeted therapy to improve survival. Early identification of the underlying etiology, coupled with the use of validated scoring systems like the KCC and MELD score, is crucial for guiding treatment decisions and evaluating transplant candidacy. While supportive care in specialized ICUs remains the foundation of management, advancements in ECLS and expanded access to LT have improved patient outcomes. Ongoing research into novel therapies, including stem cell and immunomodulatory approaches, holds promise for transforming the future landscape of ALF treatment. A coordinated, multidisciplinary approach remains essential to optimize outcomes and reduce the substantial morbidity and mortality associated with this life-threatening condition.