Acute liver failure



Acute liver failure is a syndrome of acute liver dysfunction without underlying chronic liver disease.

ALF is an uncommon condition associated with a high mortality. It is due to acute liver dysfunction in the absence of underlying chronic liver disease. ALF is characterised by coagulopathy (derangement in clotting) of hepatic origin and altered levels of consciousness due to hepatic encephalopathy (HE).

The cause of ALF is numerous, but drug-induced liver injury (DILI) is the most common reason in Europe. This may be divided into paracetamol or non-paracetamol DILI. The true burden of ALF is difficult to quantify, but it is the primary indication for liver transplantation in around 8% of cases within Europe.


There are a collection of different terminologies used to help identify and classify ALF.

Identifying ALF

ALF is characterised by the presence of coagulopathy (INR > 1.5) and HE. This is usually accompanied by transaminitis (i.e. deranged liver function tests ALT/AST) and hyperbilirubinaemia. ALF is usually initiated following a severe acute liver injury (ALI).

Key terms:

  • Acute liver failure (ALF): severe acute liver injury with development of coagulopathy (INR >1.5) and hepatic encephalopathy within 28 weeks of disease onset. Further classified into hyperacute, acute and subacute (see below).
  • Acute liver injury (ALI): severe acute liver injury from a primary liver aetiology. It is characterised by liver damage (i.e. elevated transaminases) and impaired liver function (e.g. jaundice and coagulopathy with INR > 1.5). Hepatic encephalopathy is absent.
  • Secondary liver injury (SLI): similar to ALI but no evidence of a primary liver insult. Examples include severe sepsis or ischaemic hepatitis. Management focuses on treating the underlying disease process.

The development of HE is the key differentiating factor between ALF and ALI.

Classifying ALF

ALF can be divided into hyperacute, acute, and subacute based on the speed (days/weeks) at which HE develops following the onset of jaundice. There are various definitions describing subtle differences in the timeframe. Here we describe the original classification by O'Grady et al in 1993 that has referenced in the current EASL guidelines on ALF:

  • Hyperacute: HE within 7 days of noticing jaundice. Best prognosis as much better chance of survival and spontaneous recovery.
  • Acute: HE within 8-28 days of noticing jaundice
  • Subacute: HE within 5-12 weeks of noticing jaundice (ALF may be defined up to 28 weeks). Worst prognosis as usually associated with shrunken liver and limited chance of recovery.

NOTE: HE occurring more than 28 weeks after onset of jaundice is categorised as chronic liver disease. Usually presenting with decompensated chronic liver disease (dCLD) or acute on chronic liver failure (ACLF) depending on the severity of illness


Across Europe, DILI is the most common cause of ALF.

The cause of ALF is numerous. Within Europe, the most common cause is DILI whereas worldwide the most common aetiology is viral (e.g. hepatitis A, B, E). The aetiology is important to determine prognosis and potential treatments (e.g. transplant).

Primary cause of ALF

  • Viruses (A, B, E)
  • Paracetamol
  • Non-paracetamol medications (e.g. Statins, Carbamazepine, Ecstasy)
  • Toxin-induced (e.g. Amanita phalloides - death cap mushroom that contains amatoxins and phallotoxins)
  • Budd-chiari syndrome
  • Pregnancy-related (e.g. fatty liver of pregnancy, HELLP syndrome)
  • Autoimmune hepatitis
  • Wilson’s disease

An emergency liver transplantation may be an option for these aetiologies

Secondary causes of ALF

  • Ischaemic hepatitis
  • Liver resection (post-hepatectomy liver failure)
  • Severe infection (e.g. malaria)
  • Malignant infiltration (e.g. lymphoma)
  • Heat stroke
  • Haemophagocytic syndromes

An emergency liver transplantation is not an option for these aetiologies


ALF is associated with significant morbidity and mortality.

The exact pathophysiology of ALF depends on the underlying aetiology leading to liver dysfunction. Most cases of ALF are associated with a direct insult to the liver leading to massive hepatocyte necrosis (death of tissue) and/or apoptosis (programmed cell death), which prevents the liver from carrying out its normal function.

As the condition progresses it can lead to a hyperdynamic circulatory state with low systemic vascular resistance due to a profound inflammatory response. Collectively, this causes poor peripheral perfusion and multi-organ failure. Patients also develop significant metabolic derangements (e.g. hypoglycaemia, electrolyte derangement) and are at increased risk of infection.

Marked cerebral oedema occurs, which is a major cause of morbidity and mortality in ALF. This is thought to be due to hyperammonaemia causing cytotoxic oedema and increased cerebral blood flow that disrupts cerebral autoregulation.

Clinical features

ALF is characterised by jaundice, confusion and coagulopathy.

The key clinical features in ALF are jaundice and HE. HE may manifest as confusion, altered mental status, asterixis (i.e. flapping tremor) and/or coma. Jaundice is usually obvious by looking at the skin and sclera.

In patients with suspected ALI or ALF, it is essential to look for any features of chronic liver disease (e.g. spider naevi, palmar erythema, leuconychia) that may suggest the first presentation of decompensated cirrhosis rather than ALF.

Sign & symptoms

  • Altered mental status
  • Confusion
  • Asterixis: flapping tremor suggestive of HE
  • Jaundice
  • Right upper quadrant pain (variable)
  • Hepatomegaly
  • Ascites
  • Bruising (coagulopathy)
  • GI bleeding: haematemesis, melaena
  • Hypotension and tachycardia: reduce systemic vascular resistance and hyperdynamic circulation
  • Raised intracranial pressure: papilloedema, bradycardia, hypertension, low GCS

Hepatic encephalopathy

The severity of HE can be graded using the West Haven criteria:

  • Grade I: change in behaviour with minimal change in level of consciousness. May have mild asterixis or tremor.
  • Grade II: gross disorientation, drowsiness, asterixis and inappropriate behaviour
  • Grade III: marked confusion, incoherent speech, sleeping most of the time but rousable to verbal stimuli. Asterixis less noticeable, elements of rigidity.
  • Grade IV: coma that is unresponsive to verbal or painful stimuli. Evidence of decorticate or decerebrate posturing.

Diagnostic work-up

Early transfer to a transplant centre is imperative in patients with ALF.

The initial work-up for a patient with suspected ALF involves formal clinical assessment alongside urgent blood tests, non-invasive liver screen and imaging. Collectively, this helps to differentiate ALI from ALF (by the presence of HE), determine the aetiology, investigate for underlying cirrhosis and assess how urgently they need to be transferred to a transplant centre for further work-up.

Urgent blood tests

These tests are crucial for the diagnosis of suspected ALF and to determine the severity. Bloods tests including coagulation, lactate and renal function form a key part of the referral and transplant criteria for ALF.

  • Full blood count
  • Urea & electrolytes
  • Liver function tests: including conjugated and unconjugated bilirubin
  • Bone profile
  • Blood glucose
  • Arterial ammonia
  • Arterial blood gas (pH and lactate)
  • Coagulation: urgent INR
  • Lactate dehydrogenase
  • Lipase/amylase: pancreatitis complication of ALF
  • Blood cultures: sepsis is major cause of morbidity and mortality

Non-invasive liver screen

This refers to a series of tests that are critical to determine the aetiology (e.g. viral, autoimmune). If they are all negative, an alternative cause for ALF needs to be determined (e.g. DILI). 

  • Toxicology screen: serum/urine
  • Paracetamol serum level 
  • Autoimmune markers: ANA, autoantibodies, immunoglobulins, ANCA
  • Viral screen:
    • Hepatitis A: anti-HAV IgM
    • Hepatitis B: HBsAg, anti-HBc IgM +/- HBV DNA levels
    • Hepatitis C: anti-HCV (unlikely to cause ALF - may be co-infected)
    • Hepatitis D: if positive for HBV 
    • Hepatitis E: anti-HEV IgM +/- HEV RNA levels
    • Other: CMV, EBV, HSV, VZV, Parvovirus


Diagnostic imaging of the liver is essential as part of the aetiological work up with doppler ultrasound to assess the patency of the hepatic and portal veins. It is also needed to look for evidence of pre-existing cirrhosis. Cross-sectional imaging of the abdomen (e.g. CT abdomen and pelvis) may be required to examine the liver architecture, volume, vascular integrity and exclude complications such as pancreatitis.

ALI versus ALF

The key differentiation between ALI and ALF is the development of HE. It is important to carefully screen for HE, which may involve clinical assessment, cognitive tests, arterial ammonia and electroencephalogram (EEG). 

HE can alter consciousness and lead to coma. Therefore, patients need to be regularly reviewed and considered for early transfer to intensive care (e.g. ≥grade 2 HE) where physicians are skilled in airway management. Even subtle alterations in mental status could indicate development of life-threatening ALF within the immediate future. 

Contraindications to transplant

Patients with ALF may be considered for superurgent liver transplantation. It is therefore important to determine factors that would affect the decision to undergo transplantation. This may include previous cirrhosis, which would indicate decompensated cirrhosis rather than ALF, heavy alcohol use, significant co-morbidities (e.g. major cardiac or respiratory disease) or terminal illness (e.g. cancer). 

Transfer to transplant centre

Early transfer to a transplant centre for specialist assessment and monitoring is criterial for patients with significant ALI and ALF. This allows urgent planning and assessment if the condition deteriorates. This is key even among patients who would not be suitable for transplant as it can increase the chance of survival. 

It is best for patients to be admitted to intensive care locally prior to transfer to enable a safe transfer of a critically ill patient. 

Referral criteria

The European Association for the Study of the Liver (EASL) set out guidance for when to transfer to a liver transplant centre.

Paracetamol and hyperacute aetiology

  • Arterial pH: <7.30 or bicarbonate <18 mmol/L
  • INR:  >3.0 on day 2 or >4.0 thereafter
  • Renal: Oliguria or elevated creatinine
  • Mental status: Altered consciousness (i.e. HE)
  • Glucose: Hypoglycaemia
  • Lactate: Elevated lactate unresponsive to fluid resuscitation

Non-paracetamol aetiology

  • Arterial pH:  <7.30 or bicarbonate <18 mmol/L
  • INR: >1.8
  • Renal: Oliguria or acute kidney injury
  • Serum sodium:  < 130 mmol/L
  • Mental status: HE
  • Metabolic: hypoglycaemia or metabolic acidosis
  • Bilirubin: >300 umol/L
  • Imaging: Shrinking liver size

Transplant criteria

The King’s college criteria is commonly used to help select patients to undergo liver transplantation.

Patients with ALF can be considered for superurgent listing for an emergency liver transplantation if there are no major contraindications and the patient is deemed stable enough to undergo a major operation. This is a complex decision that takes place between hepatologists, intensive care physicians and transplant surgeons.

The overall one year survival following emergency liver transplantation is around 80%. The decision to undergo transplantation needs to take into account multiple factors including aetiology, predictive survival without and following transplantation and fitness to undergo an emergency operation. 

Predictors of poor prognosis

It is imperative to identify patients early who would be suitable for transplantation and where medical therapy is suspected to fail based on prognostic markers.

Factors associated with poor prognosis and need for transplantation include:

  • Encephalopathy: any evidence of HE should prompt critical care assessment
  • Extrahepatic organ failure: particularly acute kidney injury
  • Adverse aetiology: indeterminate aetiology associated with poor survival without transplant
  • Type of presentation: subacute ALF associated with poor survival without transplant
  • Biochemical markers: the significance depends on the underlying aetiology

King’s college criteria

This refers to clinical criteria that are used to select patients to undergo emergency liver transplantation. It is largely based on the poor prognostic markers for survival without transplantation. There are different criteria used worldwide but the performance of the King’s college criteria is best characterised.

King’s college criteria

Transplantation should be considered in those patients fulfilling the King’s College criteria.

The most widely used criteria is the King's College criteria that was originally developed in 1989. Since its original publication, lactate is also used as part of the listing criteria for ALF secondary to paracetamol. A variety of other prognostic markers have also been addressed in studies.


  • Arterial pH: < 7.3 after resuscitation and > 24 h since ingestion
  • Lactate: > 3 mmol/L after resuscitation, OR
  • The 3 following criteria:
    • Hepatic encephalopathy ≥ grade 3
    • Serum creatinine > 300 umol/L
    • INR > 6.5


  • INR: > 6.5, OR
  • 3 out of 5 following criteria:
    • Aetiology: indeterminate aetiology hepatitis, drug-induced hepatitis
    • Age: < 10 years or > 40 years
    • Jaundice: Interval jaundice-encephalopathy > 7 days
    • Bilirubin: > 300 umol/L
    • INR: > 3.5


Patients with ALF should be managed in intensive care in a transplant centre.

The overall management of ALF is complex as it involves multiple systems that each require individual managements strategies within an intensive care setting.

Management principles

We outline some of the broad management principles of patients with ALF based on organ-systems.

  • Cardiovascular: fluid resuscitation +/- use of inotropic agents (increase vascular tone and contractility)
  • Respiratory: intubation and ventilation may be needed for HE or respiratory failure. Consider paracentesis to improve oxygenation. Chest physiotherapy. Extracorporeal membrane oxygenation (ECMO) may be needed in selected patients. 
  • Gastrointestinal: nutrition (NG feeding +/- total parenteral nutrition), gastric ulcer prophylaxis (proton pump inhibitor), and assess for pancreatitis. Manage GI bleeding as needed.
  • Metabolic
    • Hypoglycaemia: maintain blood glucose level 8-11 mmol/L
    • Hyponatraemia: maintain serum sodium 140-145 mmol/L. May require hypertonic saline, improves intracerebral pressure.
    • Acidosis and lactate: used as part of transplant selection criteria
    • Hypophosphataemia: suggestive of liver regeneration, good prognostic sign. Needs correction.
  • Renal: acute kidney injury is common. May require renal replacement therapy.
  • Coagulopathy: imbalance in coagulation (loss of pro and anticoagulation factors with low platelets). No increased bleeding risk. Use blood products if bleeding.
  • Sepsis: high risk of life-threatening infections including fungal. Early, aggressive treatment of infections with broad spectrum anti-microbials.
  • Neurological: may require intubation and ventilation for high grade HE due to risk of aspiration. At risk of raised intracranial pressure (ICP). Need specific raised ICP monitoring and management.
  • Liver: should be assessed and considered for urgent transplantation as discussed. 


Survival from ALF is greater than 60% and around 55% of patients will have spontaneous recovery without need for liver transplantation.

Major complications associated with ALF include sepsis due to marked immune dysfunction and progressive multi-organ failure, which includes acute kidney injury, metabolic disturbance, haemorrhage (e.g. GI Bleeding) and cerebral dysfunction (e.g. seizures, irreversible brain injury). Cerebral dysfunction is commonly the result of raised intracranial pressure. Patients are at risk of high output cardiac failure due to low vascular resistance from the widespread inflammatory response.

Last updated: October 2021
Author The Pulsenotes Team A dedicated team of UK doctors who want to make learning medicine beautifully simple.

Pulsenotes uses cookies. By continuing to browse and use this application, you are agreeing to our use of cookies. Find out more here.