Approach
ALF may be confused with acutely decompensated cirrhosis or acute-on-chronic liver failure. A critical step in establishing the diagnosis of ALF is distinguishing this condition from chronic liver failure (cirrhosis) and acute-on-chronic liver failure.[4] Cirrhosis is a highly prevalent condition, and decompensated cirrhosis can present with complications such as ascites, variceal haemorrhage, and hepatic encephalopathy. Acute-on-chronic liver failure presents with acutely decompensated cirrhosis, has a very high short-term mortality (28 days), and is mostly seen in patients with cirrhosis in the setting of superimposed liver injury, leading to profound systemic inflammation. ALF can be distinguished from decompensated cirrhosis or acute-on-chronic liver failure based on laboratory and imaging tests. This distinction is critical, as the management of each condition is significantly different.[4]
The diagnosis of ALF is established through a careful history, including: chronology of events prior to presentation; physical examination; laboratory studies. Liver imaging should also be performed if drug-induced liver injury is suspected.[30] Early recognition, diagnosis, and establishment of prognosis are paramount to providing an optimal management strategy in patients with ALF. Once the diagnosis is made, early contact with a liver transplant centre should be addressed, as all patients with ALF should be considered for possible liver transplantation.[48] Urgent cadaveric liver transplantation is the standard of care for patients with ALF.
History and physical findings
ALF is defined by the onset of jaundice, coagulopathy (INR >1.5), and hepatic encephalopathy in patients with no prior history of liver disease.[1][2][3][4] Assessment for potential exposure risks, ingestion of drugs and herbal or dietary supplements in the past 180 days, alcohol, or substance misuse, and establishment of the time course of illness, are critical.[4][30] Exposure to specific hepatotoxins, such as ingestion of Amanita phalloides mushrooms, may require specific management strategies and therapy.
Age >40 years, female sex, poor nutritional status or fasting, pregnancy, chronic hepatitis B, and the use of multiple paracetamol preparations for chronic pain are also key risk factors to be considered.
Assessment of the time course of the illness according to the interval from the onset of jaundice to the development of encephalopathy allows further classification of ALF into categories based on hyperacute (if occurring within 7 days), acute (between 8 and 21 days), or subacute presentations (between 22 days and 26 weeks).[4] Patients who present with a hyperacute time course are more likely to have a spontaneous resolution, but are also at greater risk of developing cerebral oedema and intracranial hypertension.[4]
The aetiology of ALF is not only established by history and serological assays, but also by the exclusion of alternative causes, including acute presentations of chronic liver diseases. Chronic liver diseases such as autoimmune hepatitis and chronic hepatitis B may present as an acute exacerbation with the clinical features of ALF. Abdominal pain, nausea, vomiting, and malaise are common symptoms, while right upper quadrant tenderness may present less frequently.
Hepatomegaly may be present in the setting of acute viral hepatitis, congestive heart failure with hepatic congestion, Budd-Chiari syndrome, and infiltrative malignancies. Physical examination findings may provide clues that suggest the presence of an underlying chronic liver disease, such as splenomegaly, spider angiomata, palmar erythema, and ascites.
Emphasis should be placed on determining the aetiology of ALF, as it is an important prognostic indicator and will guide further management with regards to aetiology-specific therapies.[4]
Clinical evaluation of hepatic encephalopathy
Hepatic encephalopathy is one of the defining features of ALF. Hepatic encephalopathy encompasses a spectrum of neurological and psychiatrical changes, and initial symptoms may be subtle. The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver guidelines advise using the West Haven Criteria to grade hepatic encephalopathy.[49]
Grade 1: subtly impaired awareness, sleep alterations, shortened attention span, impaired addition or subtraction, heightened mood or anxiety, oriented in time and space.
Grade 2: lethargy or apathy, disorientation for time, obvious personality change, inappropriate behaviour, dyspraxia, asterixis.
Grade 3: somnolence to semi-stupor, responsive to vocal stimuli, marked confusion, gross disorientation (disoriented in time and space), bizarre behaviour. Physical findings may include hyper-reflexia, nystagmus, clonus, and rigidity.
Grade 4: coma.
Encephalopathy grade at the time of presentation is an important factor linked to prognosis. In addition, subsequent changes in severity of hepatic encephalopathy play a role in management decisions during the course of hospitalisation for ALF, as advanced grades (3 to 4) are associated with severe complications such as cerebral oedema and intracranial hypertension.
A careful physical assessment is an important component of the initial evaluation. This should include a neurological examination to characterise the degree of hepatic encephalopathy, particularly in cases with increased severity, to assess for evidence of intracranial hypertension. The examination should include an assessment of the patient’s orientation in time and space. Patients with grade 2 hepatic encephalopathy are disorientated in time, and patients with grade 3 hepatic encephalopathy are disorientated in time and space.[49] Patients may demonstrate asterixis, a flapping movement of the hands that is elicited by extending the arms, dorsiflexing the wrist, and spreading the fingers. It is a form of negative myoclonus, where a brief loss of tone in agonist muscles is followed by a compensatory jerk in antagonist muscles.[50] Patients may develop motor signs such as hypertonia, hyper-reflexia, and a positive Babinski's sign. Extra-pyramidal signs such as bradykinesia, slow monotonous speech, and dyskinesia are common.[49] Physical exam findings associated with cerebral oedema and intracranial hypertension include abnormal pupillary reflexes, muscular rigidity, and decerebrate posturing in advanced stages. Earlier signs of intracranial hypertension (e.g., headache, visual disturbance) are not seen because cerebral oedema only occurs after grade 3/4 hepatic encephalopathy (coma) has developed.[51]
A more specialised diagnostic assessment may be performed based on suspicion of specific causes of ALF, as in the case of a slit-lamp ophthalmological examination to assess for Kayser-Fleischer rings in acute Wilson's disease. Severe non-immune intravascular haemolysis is an important feature of classic presentation of ALF due to Wilson's disease.[43]
Tests
The aetiology of ALF is primarily established by history, serological assays, laboratory studies, and imaging. Initial laboratory studies not only provide valuable prognostic information, but also identify early development of complications associated with ALF.
Initial diagnostic tests should include:
Blood tests: prothrombin time and international normalised ratio (INR) and liver function tests, viral serologies, autoimmune markers, toxicology screening, and parameters to assess overall clinical status, such as haematology, acid-base balance, and renal dysfunction.[4] Serum amylase and lipase levels should be assessed to exclude pancreatitis, which may develop as a complication of ALF; however, hyperamylasaemia may also develop as a result of renal dysfunction and multi-organ failure.[51][52][53][54][55] Although hyperamylasaemia is associated with an increased risk of mortality, it is not an independent predictor of mortality in ALF.[55]
All at-risk female patients of childbearing age should have a pregnancy test.[4]
Serum paracetamol levels should be measured in all patients.[4] Paracetamol levels can be useful when elevated; however, low paracetamol levels do not rule out paracetamol hepatotoxicity, and suspected cases should be managed accordingly. Over 50% of patients with acute liver injury or ALF attributed to paracetamol may have undetectable levels of plasma paracetamol levels.[56]
Initial imaging should include a chest x-ray to confirm possible aspiration pneumonia or to rule out other pulmonary abnormalities, and abdominal Doppler imaging to assess hepatic vein thrombosis associated with Budd-Chiari syndrome.[4] Liver imaging is also appropriate if drug-induced liver injury is suspected to assess whether there may be a competing aetiology. Abdominal ultrasound is first-line to assess whether cirrhosis, biliary obstruction or other focal liver changes are present. CT and MR cholangiography may also be useful to assess whether vascular abnormalities or pancreatobiliary disease are present.[30]
Additional diagnostic tests may include:
Polymerase chain reaction studies for hepatitis B, hepatitis C, and herpes simplex virus DNA may establish the diagnosis before serology studies become positive.
HIV test.
Serum ceruloplasmin, serum and hepatic copper levels, 24-hour urinary copper excretion, and slit-lamp ophthalmological evaluation for the presence of Kayser-Fleischer rings if Wilson's disease is suspected.[8]
Coombs test: in the presence of haemolysis, a negative Coombs test may further differentiate between Wilson's disease and autoimmune haemolysis, which is typically Coombs-positive.
Arterial ammonia levels are characteristically elevated if hepatic encephalopathy is present, although it is a non-specific test. High levels may predict an increased risk of developing intracranial hypertension.
Head computed tomography is useful for further evaluation of cerebral oedema or other underlying pathology in advanced encephalopathy.[4]
A transcranial Doppler, with estimation of cerebral perfusion pressure and intracranial pressure, may be considered in patients with grade 3 to 4 hepatic encephalopathy who are at risk of intracranial hypertension or for those in whom developing cerebral oedema is expected.[57]
Surveillance cultures: blood, urine, and sputum cultures should be obtained at regular intervals once advanced grade of encephalopathy develops.
Urinalysis and urine sodium should be obtained if renal dysfunction is present.
Liver biopsy: although a liver biopsy may provide additional information to suggest potential aetiologies of ALF in indeterminate cases, it is not a required test to confirm a diagnosis and generally does not have an impact on clinical management, outcome, or assessment of prognosis. For these reasons, liver biopsies in the setting of ALF are not usually performed.[58] An exception to this may include circumstances in which there is suspicion for infiltrative malignancy such as lymphoma or metastatic liver disease.[4][59] A liver biopsy may also be helpful in the diagnosis of conditions such as suspected autoimmune hepatitis or acute herpes simplex virus hepatitis.[4][60][61] If a drug-induced liver injury is suspected, liver biopsy may help to identify the hepatotoxic drug, based on the histological pattern(s), or determine the mechanism of injury, and it may also provide useful prognostic information.[30] If a liver biopsy is considered, a transjugular approach is preferable given the increased risk of bleeding associated with coagulopathy during ALF.[4] Type and screen of blood units should be performed in case a transfusion is needed.
Prognosis assessment
Based on the clinical findings on presentation, initial laboratory studies, and aetiology of ALF, an assessment can be made regarding the severity and prognosis associated with a course of ALF.
Aetiology is a key factor in the assessment of prognosis.[4] Paracetamol hepatotoxicity is more commonly associated with a hyperacute presentation and a higher rate of spontaneous recovery in contrast with idiosyncratic drug reactions, which may follow a subacute course and have a less favourable prognosis.[6][13] Acute hepatitis A and ischaemic hepatitis also have a relatively favourable prognosis. Acute hepatitis B, autoimmune hepatitis, Wilson's disease, Budd-Chiari syndrome, and indeterminate causes indicate a poorer prognosis.[8]
Grade 3 or 4 hepatic encephalopathy on admission to hospital indicates a poorer prognosis.
Laboratory studies including INR, bilirubin, creatinine, and negative logarithm of hydrogen ion activity are components of prognostic tools such as the King’s College Criteria. A low-factor V level in the presence of hepatic encephalopathy may be predictive of mortality, particularly in patients with ALF secondary to viral hepatitis.[62] In one prospective cohort of patients with ALF, it was noted that optimal factor V thresholds predictive of survival were >10.5% of normal in paracetamol ALF and >22% of normal in non-paracetamol ALF.[63]
Several prognostic criteria have been proposed and validated in the setting of ALF. These criteria can be instrumental in identifying patients at high risk of mortality. The most widely accepted prognostic tool is the King’s College Criteria.[64] Overall, these criteria are instrumental in selecting patients who have a high risk of mortality with ALF. However, they have limitations, and reliance upon prognostic scoring systems to determine candidacy for liver transplantation is not recommended by the American Association for the Study of Liver Diseases.[8]
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