Acute Liver Failure

Etiology

An extensive workup for the etiology of ALF is recommended, as this guides directed therapy and helps determine the outcome. Viral hepatitis and drug-induced hepatitis are the 2 most common causes of ALF worldwide.[1] Many infectious and noninfectious causes can cause acute hepatic inflammation. Etiologies of acute liver failure include:

• Drugs and toxins
  • Acetaminophen
  • Amanita phalloides
  • Complementary and alternative medicines
  • Phenytoin
  • Nitrofurantoin
  • Immune checkpoint inhibitors
  • Yellow phosphorus
• Viral causes 
  • Hepatotropic viruses
    • Hepatitis A virus
    • Hepatitis E virus
    • Hepatitis B virus (with or without hepatitis D virus)
  • Non-hepatotropic viruses
    • Epstein-Barr virus
    • Herpes simplex virus
    • Cytomegalovirus
    • Varicella zoster virus
    • Dengue virus
    • Adeno virus
    • COVID-19 virus
• Immunologic (eg, autoimmune hepatitis)
• Metabolic diseases (eg, Wilson disease)
• Pregnancy-related conditions, eg, acute fatty liver of pregnancy and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome
• Ischemic and vascular conditions
  • Ischaemic hepatitis
  • Acute Budd-Chiari syndrome
  • Sinusoidal obstruction syndrome
• Miscellaneous conditions
  • Malignant infiltration (eg, metastasis from breast cancer, small cell lung cancer, and lymphoma) of the liver
  • Reye syndrome
  • Primary graft nonfunction after liver transplantation
  • Hemophagocytic lymphohistiocytosis
  • Liver resection [8][9][10][11][12][13][14][15]

Drug and Toxin-Induced Hepatitis

Drug-induced hepatitis contributes to nearly half of all ALF cases in the United States, with acetaminophen representing the leading cause. Acetaminophen toxicity follows a dose-dependent pattern and becomes particularly dangerous in individuals with concurrent alcohol use or malnourishment, where unintentional overdose frequently leads to hepatotoxicity and eventual liver failure.[16] While some drug-induced liver injuries stem from idiosyncratic reactions, these occur infrequently and typically involve unpredictable immune or metabolic responses.

Dose-dependent hepatotoxicity often results from agents such as acetaminophen (paracetamol), which in excessive amounts overwhelms hepatic metabolism and leads to hepatocellular necrosis. In contrast, non-dose-dependent reactions are typically idiosyncratic and frequently associated with antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs (NSAIDs), statins, and various herbal or nutritional supplements.

Several toxins can also induce hepatitis. Among these, Amanita phalloides mushrooms rank among the most lethal, causing fulminant hepatic failure through potent hepatotoxins. Other harmful agents include carbon tetrachloride, certain herbal and dietary supplements, and even marine toxins, such as those found in sea anemone stings. Prompt identification of the causative agent plays a critical role in patient management and can significantly influence prognosis.

Acute Viral Hepatitis

AVH etiologies are the leading cause of ALF, and of these conditions, hepatitis E, which accounts for 40% of cases, is the most common cause of ALF in developing countries.[1][17][18] HBV infection could cause liver failure from both acute infections, as well as from reactivation of HBV following initiation of immunosuppressive therapy. Coinfection with both HBV and hepatitis C could lead to ALF, although ALF is rarely seen with hepatitis C alone. Sometimes, the etiology remains elusive and is usually caused by nonhepatotropic viruses.[1][19][20][21][22][23]

Epidemiology

The incidence of the underlying etiologies of ALF demonstrates regional variability. HAV, HBV, and HEV are the leading causes of ALF worldwide and are primarily seen in low-economic countries compared to drug-induced liver injury in high-economic countries.[24][25] Worldwide, the World Health Organization (WHO) estimates that 1 in 3 people have been infected with either HBV or HCV. In highly endemic areas, HAV has affected more than 90% of children by age 10, with the majority of cases in low-income regions.[26][24]

A recent review of the epidemiology of ALF over the past 50 years reveals that the relative incidence of ALF secondary to HAV and HBV has declined, while that of acetaminophen has increased, mainly in the United States and Western Europe. Approximately 45.7% of ALF cases in North America and 65.4% of ALF cases in the United Kingdom were drug-induced (specifically acetaminophen) [11], compared to hepatotropic AVH-associated ALF (eg, HBV and HEV), which accounted for 12% of cases in the United States but up to 50% of cases in Japan, 68% of cases in India, and 91% of cases in Bangladesh.[27][28][29][25]

The incidence of HAV and HBV has decreased significantly since the introduction of vaccines. A slight increase in HAV cases has been observed recently, mostly from isolated food-related outbreaks, individuals who use drugs, and the homeless population.[11] Currently, individuals aged 40 and older have the highest rate of acute HBV related to hepatitis risk factors, including injection drug use, multiple sex partners, and lack of prior vaccination. Additionally, HDV coinfection is a significant risk factor for ALF due to HBV. Studies have shown that an estimated 20% of patients coinfected with acute HBV and HDV develop ALF, and up to 80% of these patients die without a liver transplant.[1] HCV has been steadily increasing since 2010, particularly in adults 20 to 40 years old, secondary to injection drug use related to the opioid crisis, as well as improved surveillance.[30]

Other conditions causing acute hepatitis and ALF are much less common and are likely under-reported, eg, nonhepatotropic viral infections, drug-induced liver injury, and autoimmune diseases.[10][12][26] For instance, the etiology of ALF cases in the United States is reported to be mushroom toxicity in approximately 50 individuals annually, autoimmune hepatitis in 3% to 6% of patients, and malignant infiltration in 1.4% of patients.[1]

Pathophysiology

The pathophysiology depends on the etiology of the ALF. ALF develops following primary hepatocyte injury induced by hepatotropic viruses, drugs, alcohol, or other hepatotoxicants acting through intrinsic and extrinsic cell death pathways. Primary injury disrupts Kupffer cell tolerance, triggering the activation of these cells and the release of proinflammatory mediators.[25] This process recruits circulating monocytes and neutrophils while damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) amplify inflammation, resulting in secondary immune-mediated hepatocyte necrosis and mitochondrial dysfunction.

Necrotic hepatocytes release additional DAMPs, sustaining activation of Kupffer cells, natural killer cells, and natural killer T cells. These activated immune cells secrete proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, CXCL10), promoting further leukocyte infiltration and hepatocellular injury. Concurrently, the number of Kupffer cells and their phagocytic capacity decline, impairing pathogen clearance and increasing susceptibility to secondary infections, particularly from Escherichia coli and Candida species. Despite inherent hepatic regenerative capacity, persistent immune activation, hepatocyte senescence, and defective clearance mechanisms may precipitate uncontrolled inflammation and regeneration failure, culminating in ALF. The resulting systemic immune, metabolic, and hemodynamic dysregulation ultimately leads to multiorgan failure.

Most cases of ALF will have massive hepatocyte necrosis and apoptosis, leading to liver failure. Hepatocyte necrosis occurs due to adenosine triphosphate (ATP) depletion, which causes cellular swelling and cell membrane disruption. The pathophysiology of cerebral edema and hepatic encephalopathy seen in ALF is multifactorial, eg, altered blood-brain barrier secondary to inflammatory mediators leading to microglial activation, accumulation of glutamine secondary to ammonia crossing the blood-brain barrier, and subsequent oxidative stress leading to depletion of ATP and guanosine triphosphate, ultimately leading to astrocyte swelling and cerebral edema.[31][32][33][34]

Histopathology

If evaluation through history, clinical examination, and laboratory and imaging studies is inconclusive, a transjugular liver biopsy can be performed to ascertain the specific etiology of ALF. The histopathology of acute hepatitis is determined by the underlying etiology causing the hepatocellular injury. Acute hepatitis secondary to acetaminophen overdose demonstrates characteristic histological features eg, central to central bridging necrosis and minimal inflammatory cell infiltrates.

The histopathologic features of acute hepatitis secondary to viral infections usually show intranuclear viral inclusions and surrounding neutrophils. Classical historical features of autoimmune hepatitis include portal inflammation and interface hepatitis, formally known as piecemeal necrosis, which is characterized by the presence of portal inflammatory cells between the portal and liver parenchyma.[10] Additionally, special stains for HBV, CMV, EBV, adenovirus hepatitis, HSV, and immune-histopathological stains should be considered.

Increased hepatic copper concentrations and Mallory-Denk bodies are the classical histopathological liver biopsy findings in patients with Wilson's disease.[35] 

History and Physical

Clinical History

Ascertaining the etiology of ALF is of the utmost importance in its clinical management, making it crucial to obtain a detailed history that should include the duration of the presenting illness, travel history, and assessment for high-risk activities like intravenous drug use, alcohol consumption, sexual history, prior blood-product transfusion history, or recent food intake. Inquiring about drug history, including recent or current prescription medications, over-the-counter medications, acetaminophen (paracetamol), common cough/cold medications that contain acetaminophen, multivitamins, and herbal/nutritional supplements, is also essential. Additional clinical history that should be obtained includes:

• Any history of hepatic disease or hepatic decompensation
• Any concomitant relevant chronic health conditions
• The timeline of symptom onset, particularly in patients with acetaminophen toxicity
• Family history, especially Wilson's disease and thrombotic disorders
• Recent surgeries where anesthetic agents could be implicated as the possible ALF etiology

Patients with AVH commonly present with fever, malaise, fatigue, loss of appetite, vomiting, diarrhea, and abdominal pain. Patients may also report yellowish discoloration of their sclera (icterus) and skin (jaundice), dark-colored urine, and light-colored stools. Most ALF patients with AVH will present with common clinical symptoms (eg, fatigue and nausea) before more severe liver damage features (eg, jaundice) become evident.[1]

Clinical Examination

Physical exam findings of ALF may include hypotension, altered mental status, fever (with infectious etiology), right upper quadrant discomfort, hepatomegaly, tenderness with nausea, and features of jaundice and fluid overload.[36][37] Mental status examination using the West-Haven Criteria should also be performed in patients with ALF.[1]

Additionally, depending on the underlying etiology, physical exam findings can range from the presence of icterus and jaundice to signs of acute encephalopathy, seizures, bleeding diathesis, hypotension, and other manifestations related to multiple organ failure.[38][12] Signs of chronic liver disease, including caput medusae, spider nevi, palmar erythema, ascites, Dupuytren contracture, gynecomastia, and hepatic encephalopathy, can be seen in patients presenting with acute-on-chronic liver disease and are crucial in ruling them out.

Evaluation

Laboratory Studies

When evaluating patients with ALF, differentiating between acute and chronic hepatitis is essential. Laboratory studies including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transferase (GGT), lactate dehydrogenase, bilirubin, international normalized ratio (INR), and albumin determine the normal functioning of the liver and any abnormalities in these tests is indicative of injury to the hepatocytes from infectious and noninfectious causes.

Common findings of ALF include prolonged INR ≥1.5, often elevated bilirubin and aminotransferases, thrombocytopenia, with anemia, hypoglycemia, elevated ammonia, and features of acute renal injury with elevated serum creatinine, and dyselectrolytemia (eg, hypokalemia and hypophosphatemia) is common. The possible etiology and severity of the hepatocellular injury can be determined based on the laboratory abnormalities identified.[39][40][41] Clinicians should also maintain suspicion for an extrahepatic process that could be contributing to abnormal liver function tests, eg, pregnancy, lactic acidosis, sepsis, and cardiac dysfunction. Certain laboratory study findings may suggest the following liver dysfunctions:

• Hepatocyte metabolic/catabolic dysfunction
  • Serum bilirubin: Synthesized primarily in the reticuloendothelial cells from the breakdown of heme-containing proteins, serum bilirubin levels can be abnormally increased in liver diseases secondary to impaired uptake, impaired conjugation, or due to leak from damaged hepatocytes or bile ducts.
  • Ammonia: Ammonia levels may be elevated due to hepatic metabolic impairment. Measurement of arterial ammonia levels is controversial, but in ALF, arterial ammonia levels have proven to be prognostic. 

• Hepatocellular injury
  • Serum transaminases: Aminotransferase elevation, including AST, also called serum glutamic-oxaloacetic transaminase (SGOT), and ALT, also called serum glutamic pyruvic transaminase (SGPT), is suggestive of hepatocellular injury.
    • Marked elevations >5 times the upper limit of normal or >500 IU/L are suggestive of extensive hepatocellular injury. This finding is commonly encountered in acute hepatitis, drug-induced liver injury, eg, acetaminophen overdose, profound ischemia to the liver, hepatic necrosis, or cases of severe autoimmune hepatitis.
    • Milder elevations are considered <5 times the upper limit of normal or <500 IU/L and can result from a variety of liver injuries or disorders. Some of these disorders can overlap with acute causes but are often associated with more chronic hepatitis or nonhepatic causes, examples of which include smoldering inflammation from autoimmune disorders, hemochromatosis, Wilson disease, and drug-induced liver injury.

• Synthetic dysfunction 
  • Prothrombin time: Elevated PT occurs when liver injury decreases the synthetic function of the vitamin K-dependent coagulation factors (II, VII, IX, X). Prolongation of the INR >1.5 is considered a key component in making a diagnosis of acute liver failure.[27] Prolongation of PT/INR occurs within hours to days of liver injury, making it a better marker than albumin to determine the liver's synthetic function. INR >6.5 is a single criterion to list for emergency liver transplantation. 
  • Albumin: Decreased albumin is not specific to liver injury; therefore, its utility in the diagnosis of acute hepatitis is limited. 

Although liver function tests give an initial idea about the possible etiology and severity of the underlying hepatocellular injury, further evaluation with specific diagnostic tests is recommended to ascertain the etiology of acute hepatitis. Additional evaluation studies are guided by the following degrees of elevation of the ALT and AST, based on the guidelines published by the American College of Gastroenterology (ACG):

• Mild elevation in serum transaminases (<5 times the upper limit of normal): ACG guidelines recommend checking a complete blood count, AST, ALT, alkaline phosphatase, total bilirubin, albumin, PT/INR, comprehensive hepatitis panel that includes hepatitis A immunoglobulin M antibody, hepatitis B surface antigen, hepatitis B core antibody (IgM), hepatitis B surface antibody and hepatitis C antibody, and iron studies (eg, serum iron, total iron-binding capacity, serum transferrin saturation, and serum ferritin) and imaging with an abdominal ultrasound examination.[42]

• Severe elevation in serum transaminases (>15 times the upper limit of normal) or massive ALT elevations (>10000 U/L): ACG guidelines recommend checking for EBV, CMV, ceruloplasmin, autoimmune markers (eg, antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney microsomal immunoglobulin G antibodies), drug panel tests that include acetaminophen, and urine toxicology. Guidelines also recommend performing a sonographic Doppler study of the hepatic vein, portal vein, and hepatic artery to rule out vascular occlusion (eg, Budd-Chiari syndrome).[42]

Additional laboratory findings

Other diagnostic laboratory findings associated with ALF include:

• Arterial blood gas analysis: Lactate levels are part of the King's College Criteria of ALF. Metabolic acidosis also has a prognostic value.[43][44]
• Blood sugar levels: Hypoglycemia is very common in ALF, and close monitoring of blood sugar levels is advised [45][46]
• Hemogram: Wilson disease can have Coombs-negative hemolytic anemia. A low platelet count in ALF is seen chiefly due to consumption coagulation and should not be confused with chronic liver disease.

Imaging Studies 

Abdominal imaging to determine the presence of preexisting liver disease (cirrhosis, features of portal hypertension or hepatocellular carcinoma), vascular thrombosis as in Budd-Chiari syndrome, lymph nodes, and spleen is vital. Abdominal sonogram with Doppler could be considered in patients with concomitant renal injury and vascular thrombosis.[42] Noting the liver span serially will help in the prognostication of ALF. Brain CT or magnetic resonance imaging helps rule out the organic etiology of altered mental status, for documenting cerebral edema and, importantly, to detect imminent coning and brain death, while chest imaging will help rule out pulmonary edema or pneumonia.[42][47]

Noninvasive Bedside Assessments in Acute Liver Failure

Optic nerve sheath diameter (ONSD)

Optic nerve sheath diameter (ONSD) measurement exploits the anatomical continuity between the optic nerve sheath and dura mater, with dilatation occurring in response to elevated intracranial pressure. An ONSD exceeding 6 mm indicates an elevated intracranial pressure and enables the detection of cerebral edema preceding clinical manifestations.[48]

Transcranial Doppler ultrasound

Doppler ultrasound assessment of middle cerebral artery flow velocity and pulsatility index provides prognostic information, with a pulsatility index >1.2 correlating with increased mortality and transplantation likelihood.[49]

Pupillometry

Quantitative pupillary assessment facilitates early identification of neurological deterioration through objective measurement of pupil size and reactivity.[50]

Continuous electroencephalography

Continuous electroencephalogram (EEG) monitoring enables the detection of nonconvulsive seizures and the characterization of evolving patterns of cerebral dysfunction.[51]

Treatment / Management

The management of ALF consists of supportive care, prevention and management of complications, specific treatment when the exact etiology is known, and determination of prognosis and the need for liver support, including possible liver transplantation.[52][53][54][40][41][42] All patients should be hospitalized, preferably at a center with facilities and expertise for liver transplants.(B3)

Supportive and Preventive Care

Hemodynamics

Assessment of hemodynamic stability and the need for intravenous fluids to maintain acid-base balance and normal electrolyte levels is essential. Acute liver failure presents characteristic haemodynamic disturbances including systemic and splanchnic vasodilatation, reduced mean arterial pressure, elevated cardiac output, and effective hypovolaemia. Disease progression frequently involves capillary leak syndrome, third-space fluid accumulation, oliguria, and pulmonary complications secondary to interstitial oedema and progressive vasodilatation.

Fluid resuscitation strategy

Given the dual risks of hypovolaemia and fluid overload in precipitating organ dysfunction, fluid therapy requires guidance through dynamic indices, including arterial lactate concentrations, urine output, and point-of-care ultrasonography where available. Balanced crystalloids are preferred over normal saline to minimize hyperchloraemic acidosis risk. Although 4% albumin demonstrates adverse outcomes in traumatic brain injury populations, 4% to 5% albumin may be considered in severe hypoalbuminaemia.

Vasopressor management

Noradrenaline serves as the preferred vasopressor in cases of hypotension unresponsive to fluid resuscitation. This agent effectively maintains both hepatic and peripheral perfusion while minimizing the risk of tachycardia, making it especially suitable for patients with acute liver failure. Achieving a target mean arterial pressure between 70 and 80 mm Hg remains essential, particularly in those with elevated ICP, to ensure adequate cerebral perfusion pressure and to prevent cerebral hypoxia.

Careful titration of vasopressors is crucial, as indiscriminate use increases the risk of ischemic complications. Maintaining hemodynamic stability with the lowest effective dose supports organ function and reduces the likelihood of secondary injury. The balance between adequate perfusion and avoidance of excessive vasoconstriction underpins the safe and effective use of noradrenaline in critically ill patients.

Management of cerebral edema

Minimizing ICP elevation requires careful attention to orotracheal suctioning techniques. Gentle and infrequent suctioning helps reduce stimulation and prevents sudden spikes in ICP, making this approach critically important in the care of patients with ALF and cerebral edema risk. Alongside minimal stimulation, frequent glucose monitoring remains essential to detect and prevent hypoglycemic episodes, which can exacerbate neurological impairment.

Early identification of neurological deterioration holds vital importance for initiating timely therapeutic measures. Delays in recognition may result in irreversible cerebral damage and poor outcomes. Consistent neurological assessments and vigilance for subtle changes in mental status enhance the likelihood of prompt intervention. Additional strategies for managing cerebral edema extend beyond suctioning and glucose control, focusing on comprehensive supportive care tailored to preserving cerebral perfusion and preventing further increases in ICP.[55][56] Other interventions for managing cerebral edema include the following strategies. 

N-acetylcysteine therapy

N-acetylcysteine functions as the first-line treatment for paracetamol-induced acute liver failure, offering well-established hepatoprotective effects through replenishment of glutathione and reduction of oxidative stress. In addition to its role in managing paracetamol toxicity, N-acetylcysteine also demonstrates therapeutic benefit in nonparacetamol-related acute liver failure, particularly among patients presenting with early-stage encephalopathy (grades 1–2).

Evidence from meta-analyses supports the use of this approach in enhancing transplant-free survival and reducing the length of hospitalization in this patient group. Despite these advantages, N-acetylcysteine has not shown a significant impact on overall survival. However, its favorable safety profile and potential to improve short-term outcomes reinforce its role in the early management of acute liver failure across various etiologies.[57](A1)

The standard dosing protocol of N-acetylcysteine is as follows:

• Loading dose: 150 mg/kg administered over 1 hour
• Maintenance: 12.5 mg/kg/hour for 4 hours
• Continuation: 6.25 mg/kg/hour for 67 hours

Electrolyte optimization

Serum sodium management targets concentrations of 145 to 155 mEq/L, which can be achieved through the administration of hypertonic saline or mannitol. Both agents demonstrate equivalent efficacy in intracranial pressure reduction, though mannitol carries an increased risk of acute kidney injury and rebound intracranial hypertension.[58][59](A1)

Phosphate homeostasis significantly influences recovery outcomes. Hypophosphatemia (<2.5 mg/dL) correlates with improved recovery rates, whilst severe hyperphosphatemia (>5 mg/dL) precludes neurological recovery. Phosphate replacement therapy demonstrates beneficial outcomes in patients with low-normal phosphate concentrations.[60][61]

Hyperammonaemia management

Current evidence does not support the therapeutic use of L-ornithine L-aspartate, lactulose, or rifaximin in managing hyperammonemia associated with ALF. These agents, commonly employed in chronic liver disease for reducing ammonia levels and treating hepatic encephalopathy, have not demonstrated clinical benefit in the setting of ALF. The pathophysiology of hyperammonemia in acute liver failure differs significantly from chronic conditions, limiting the effectiveness of these treatments in this context. The focus remains on supportive measures and targeted management strategies tailored to the acute presentation.[62]

Continuous renal replacement therapy

High-volume continuous renal replacement therapy (90 mL/kg/hour) demonstrates superior ammonia clearance compared to conventional low-volume protocols (35 mL/kg/hour). Early initiation, within 6 to 12 hours of presentation, is associated with reduced ammonia concentrations, enhanced transplant-free survival, and improved intensive care unit discharge rates without the need for transplantation.

Meta-analytical data reveal a 17% improvement in overall survival and a 27% enhancement in transplant-free survival. Treatment duration appears more predictive of outcomes than therapy intensity. The data on the role of continuous renal replacement therapy (CRRT) in ALF is evolving. 

Therapeutic hypothermia

Mild therapeutic hypothermia, maintained between 32 and 35?°C, may help mitigate cerebral edema by lowering concentrations of ammonia, glutamate, and lactate. This intervention also contributes to reduced oxidative and nitrosative stress and enhances cerebral hemodynamics. Despite these potential benefits, current evidence remains inconclusive, particularly in patients with high-grade encephalopathy. Further randomized controlled trials are needed to determine the efficacy and safety of therapeutic hypothermia in this clinical setting.

Mechanical ventilation

Patients presenting with encephalopathy exceeding grade 2 require mechanical ventilation to protect the airway and control intracranial pressure. Targeted hyperventilation in these cases aims to maintain arterial PaCO2 between 25 and 30 mm?Hg, promoting cerebral vasoconstriction and reducing ICP. Careful monitoring ensures the effectiveness of ventilation without compromising cerebral perfusion.

Decompressive procedures

Hepatectomy and cranial decompression remain experimental interventions rarely employed in clinical practice and do not constitute standard therapeutic approaches.

Etiology-Based Acute Liver Failure Management

The management of ALF varies based on the etiology causing the acute injury to the hepatocytes. Patients with suspected autoimmune hepatitis may benefit from intravenous methylprednisolone at a dose of 60 mg/day. Patients with identifiable Wilson disease or known hepatic vein thrombosis as the etiology for ALF should be considered for a liver transplant. Those with Budd-Chiari syndrome should be considered for venoplasty, stenting, or direct intrahepatic portosystemic shunt placement. In pregnant patients with ALF, likely secondary to the acute fatty liver of pregnancy or HELLP syndrome, prompt delivery of the fetus is recommended. Also, if ALF does not resolve, liver transplantation should be considered.

Acute viral hepatitis

HAV and HEV are the most common infectious causes of acute hepatitis and usually have a self-limited clinical course, resolving in 2 to 4 weeks with supportive treatment that includes intravenous (IV) fluids, antiemetics, and symptomatic treatment. Patients with HAV and HEV-associated ALF are primarily treated with supportive care as no specific antivirals are known to be effective; however, those with acute or reactivated HBV should receive nucleotide analogs. Patients should avoid the use of alcohol and other potentially hepatotoxic medications and over-the-counter supplements. Clinicians should also advise patients on how to reduce transmission risks.[63] 

Patients with herpes hepatitis or varicella zoster-related ALF should receive acyclovir 5 to 10 mg/kg IV every 8 hours. Patients with hepatitis due to cytomegalovirus should be given IV ganciclovir at a dosage of 5 mg/kg every 12 hours.

Acetaminophen hepatotoxicity 

Acute acetaminophen hepatotoxicity due to overdose ingestion is a common cause of acute hepatitis leading to ALF that should be considered in all patients presenting with ALF clinical features. Acetaminophen-induced ALF requires prompt, aggressive treatment to reduce patient morbidity and mortality. In patients presenting within 4 hours of ingestion, 1 to 2 g/kg activated charcoal may be administered depending on the patient's level of consciousness.[1]

However, N-acetylcysteine is the primary treatment for acetaminophen-induced ALF, especially in patients with an unknown time of ingestion.[1] N-acetylcysteine administration guidelines have been revised several times due to evolving clinical issues regarding acetaminophen poisoning, including single or repeated ingestions, extended-release formulations, coingestion of other medications (eg, anticholinergics or opioids), patient factors (eg, age, pregnancy, and weight). Subsequently, several protocols have been established for acute acetaminophen intoxication; however, studies comparing the effectiveness of these protocols are lacking. Therefore, recent guidelines have only recommended that clinicians administer at least 300 mg/kg of N-acetylcysteine orally or IV within the first 20 to 24 hours, regardless of the protocol used.[64](B3)

In general, oral or IV N-acetylcysteine protocols can be used based on the clinical scenario; the Rumack-Matthew nomogram guides the decision on when to begin treatment. Therapy should only be discontinued after patients meet N-acetylcysteine-stopping criteria (eg, patient clinical response and improvement of serum aminotransferase levels).[64] Please see StatPearls' companion resource, "N-Acetylcysteine," for more information. Treatment with N-acetylcysteine is also recommended for all patients with acute liver failure except ischemic hepatitis, with or without evidence of acetaminophen overdose.[11][12][27] Rising or falling serum aminotransferases, along with progressively worsening coagulopathy, indicate hepatic necrosis and progression of ALF, with a likely need for liver transplantation. N-acetylcysteine is also indicated for patients with ALF due to other causes, except perhaps ischemic hepatitis, and is particularly useful in those with early grades of encephalopathy.(A1)

Management of Acute Liver Failure Complications

ALF management is also tailored to treating and preventing complications that are frequently associated with this condition. The following interventions should be implemented to avoid the development of multiorgan dysfunction, which is critical:

• Renal failure: This complication may occur due to hypovolemia, acute tubular necrosis, or hepatorenal syndrome. Vasopressor therapy with norepinephrine or dopamine is indicated in severe hypotension. Renal replacement may be considered as a bridge for a possible liver transplant. Continuous renal replacement therapy is preferred to hemodialysis in critically ill patients.[65]

• Sepsis: Broad-spectrum antibiotics should be used to treat sepsis, including aspiration pneumonia and fever. Blood, sputum, and urine surveillance cultures should be obtained in all patients with ALF.[66]

• Metabolic disorders: Hypoglycemia occurs due to impaired glycogen production and gluconeogenesis and will need continuous infusions of 10% to 20% glucose. Hypophosphatemia resulting from ATP consumption in the setting of hepatocyte necrosis requires aggressive repletion. Alkalosis in ALF is due to hyperventilation, and acidosis with a pH <7.3 portends 95% mortality in acetaminophen overdose if the patient does not undergo a liver transplant. Hypoxemia may occur due to aspiration, acute respiratory distress syndrome, or pulmonary hemorrhage. Patients with encephalopathy greater than grade 2 should undergo endotracheal intubation for airway protection. Seizure-like activity may be treated with phenytoin or benzodiazepines.

• Coagulopathy: Like encephalopathy, coagulopathy is also a defining feature of ALF. Bleeding events are rare despite the presence of severe coagulopathy. Hence, routine correction of coagulopathy is not recommended unless in the setting of overt bleeding or before invasive procedures. 

Liver Support and Liver Transplantation

Patients with acute hepatitis progressing to ALF, defined by the presence of hepatic encephalopathy and coagulopathy with an INR >1.5, require prompt evaluation by a hepatology team. Early discussion with a liver transplant center becomes essential to assess the potential need for transfer. The underlying etiology of ALF and predicted prognosis can assist clinicians in determining the likelihood of spontaneous recovery versus the necessity for liver transplantation. Several validated selection tools, eg, the King's College Criteria, provide clinical guidance for transplant decision-making.[10][11][12]

Extracorporeal liver-assist devices have undergone evaluation in clinical trials to support patients with ALF by performing detoxification and partial synthetic function replacement. Trials involving the molecular adsorbent recirculating system (MARS) have demonstrated no improvement in overall survival. The role of CRRT in this context has been previously addressed.

High-volume therapeutic plasma exchange (TPE) has shown promise in multicenter trials, where patients receiving TPE experienced improved hemodynamic stability, reduced vasopressor requirements, and better cerebral perfusion. Neurological improvements and reductions in hepatic encephalopathy severity were also observed. A randomized trial evaluating early TPE demonstrated reductions in inflammatory markers and normalization of coagulation profiles. A meta-analysis of 5 studies confirmed improved 30-day and overall survival with TPE compared to standard therapy. Although the American Society for Apheresis supports TPE for ALF management, clinical use remains limited, and no consensus exists regarding optimal treatment protocols. A recent meta-analysis reported no significant survival benefit but confirmed enhanced hemodynamic stability. Further randomized controlled trials are necessary to clarify the role, timing, and ideal exchange volume of TPE in ALF care. Dynamic prognostic tools that incorporate TPE-related changes in laboratory markers and organ failure scores may help refine transplant evaluation strategies.[67][68][69][70][71](A1)

Liver transplantation continues to represent the definitive therapeutic intervention for carefully selected ALF patients. Due to the urgency and severity of ALF, the United States Organ Procurement and Transplant Network classifies these cases under Status 1A, granting the highest allocation priority regardless of Model for End-Stage Liver Disease (MELD) score. Criteria for Status 1A listing include the need for kidney replacement therapy, mechanical ventilation, or an INR >2. Other conditions granted equivalent prioritization include acute decompensated Wilson disease (managed similarly to ALF), primary graft nonfunction, and post-transplant hepatic artery thrombosis.

Current data indicate that approximately 30% of ALF patients undergo liver transplantation. The critical condition of these patients increases the risk of posttransplant complications, especially infections and sepsis, which remain the leading causes of allograft failure in this group. Criteria for delisting commonly include clinical recovery with medical management, active infections, limited organ availability (notably in living donor transplants), cerebral herniation, or irreversible neurological injury, evidenced by absent middle cerebral artery flow on transcranial Doppler ultrasound, fixed and nonreactive pupils, uncal herniation, or multiorgan failure. Although renal function typically recovers well after transplantation, approximately 15% of survivors may experience persistent neurological deficits.[72][73][74](B3)

Differential Diagnosis

In addition to acute hepatitis etiologies, other conditions causing secondary injury from extrahepatic or nonhepatic etiologies should also be assessed among the differential diagnoses (eg, choledocholithiasis, biliary or pancreatic malignancies, liver metastases, sepsis, systemic hypotension, hepatic artery thrombosis, and congestive heart failure.[40][12] Additional differential diagnoses that should be considered include:

• Acute fatty liver of pregnancy
• Amanita phalloides (mushroom) poisoning
• Bacillus cereus toxin
• Fructose intolerance
• Galactosemia
• HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome of pregnancy
• Hemorrhagic viruses (Ebola virus, Lassa virus, and Marburg virus)
• Idiopathic drug reaction (hypersensitivity)
• Neonatal iron storage disease
• Tyrosinemia

Prognosis

The expected clinical outcomes have undergone drastic changes since ALF was first defined approximately 50 years ago. The current 1-year survival rate of patients, including those undergoing liver transplantation, is greater than 65%. In the past, studies from the United States and Europe had indicated a lower 1-year survival rate of patients with ALF receiving a liver transplant when compared to their counterparts in patients with cirrhosis. However, the 2012 United States and Europe registry indicates a higher survival rate of up to 79% at 1 year and 72% at 5 years.

The decision-making process surrounding liver transplantation in ALF patients requires precise temporal considerations. The liver's potential for spontaneous regeneration in the absence of underlying chronic pathology distinguishes ALF from other indications for transplantation. However, this regenerative potential must be balanced against the progressive deterioration that occurs when recovery fails to materialize. Delayed transplantation may result in the development of septic complications and multiorgan system dysfunction, significantly compromising patient survival. Conversely, premature transplantation subjects patients to unnecessary surgical risks and lifelong immunosuppression when spontaneous recovery might have occurred.

Liver Failure Prognostic Tools

The specific etiology of acute liver failure is also an essential predictor for spontaneous recovery. Approximately 75% of patients spontaneously recover from acetaminophen (paracetamol) induced failure, but only about 40% spontaneously recover from other causes.[11] King's College criteria demonstrate exceptional specificity, ranging from 98% to 100%, indicating a high degree of accuracy in identifying patients who are unlikely to recover spontaneously. However, the sensitivity of  King's College criteria is substantially lower at approximately 58%, suggesting that these criteria do not identify a significant proportion of patients who will not recover. The King's College criteria were developed as a static prognostic model during an era predating the widespread availability of liver support technologies and were primarily derived from populations with nonviral etiologies of ALF. Comparative analyses have demonstrated superior performance of King's College criteria relative to the MELD score in predicting mortality among patients with acetaminophen-induced ALF. Conversely, MELD scoring has shown superior prognostic accuracy compared to King's College criteria in non-acetaminophen-related ALF cases.[12]

The Acute Liver Failure Early Dynamic (ALFED) model utilizes dynamic variables assessed over 3 days, thereby accounting for disease progression and enhancing prognostic accuracy. The Acute Liver Failure Study Group (ALFSG) model incorporates multiple clinical variables, including hepatic encephalopathy grade, ALF etiology, vasopressor requirement, and logarithmically transformed values of the international normalized ratio (INR) and serum bilirubin. Other useful prognostic criteria include Clichy criteria (presence of hepatic encephalopathy along with a Factor V level lower than 20% to 30% of normal, MELD score higher than 30, and Acute Physiology and Chronic Health Evaluation (APACHE) II score higher than 15.[75][76] The field of ALF prognostication requires continued advancement through multiple avenues of investigation. Liver volumetry represents a promising adjunctive tool for prognostic assessment; however, its clinical utility requires validation in larger, multicenter cohorts before its routine implementation.

Complications

ALF often leads to neurological issues like hyperammonemia and hepatic encephalopathy, which can escalate to cerebral edema and elevated intracranial pressure, posing risks of brain injury and death. These types of complications necessitate intensive care monitoring, intubation, and targeted management in specialized centers. ALF-related coagulopathy, hemodynamic instability, and infection are also severe ALF complications. ALF-induced renal failure is also common.[1]