Acute Liver Failure
Last updated 4th March 2020 - Tom Heaton
The liver is an essential organ with a wide variety of functions.
It’s regenerative role is impressive but it is still susceptible to acute insults that may lead to failure.
There is some overlap with an acute deterioration of chronic disease, although there are differences between these and that is considered in conjunction with chronic liver disease.
The profile of acute liver failure is generally described based on the speed of onset of encephalopathy from the time of onset of jaundice (O’Grady system):
It’s regenerative role is impressive but it is still susceptible to acute insults that may lead to failure.
There is some overlap with an acute deterioration of chronic disease, although there are differences between these and that is considered in conjunction with chronic liver disease.
The profile of acute liver failure is generally described based on the speed of onset of encephalopathy from the time of onset of jaundice (O’Grady system):
- Hyperacute (<1 week)
- Acute (1-4 weeks)
- Subacute (4-12 weeks)
Aetiology
This can be divided into causative agent
When considering the time-frame:
Hyperacute
Acute
Subacute
- Drug
- Paracetamol
- Recreational - alcohol, ecstasy, methamphetamines
- Drug reactions - antibiotics, anticonvulsants, anti-TB, halothane
- Paracetamol
- Infection
- Viral hepatitides (A, B, D, E)
- Viruses - CMV, EBV, HSV
- Viral hepatitides (A, B, D, E)
- Non-drug poisoning - Mushroom (Amanita phalloides)
- Vascular
- Ischaemic
- Budd-Chiari syndrome
- Ischaemic
- Wilson’s disease
- Neoplasms
- Autoimmune
- Post surgical resection
- Pregnancy
When considering the time-frame:
Hyperacute
- Paracetamol OD
- Deathcap mushroom poisoning
- Ischaemia
Acute
- Hepatitides
- Idiosyncratic drug reactions
Subacute
- Drug reactions
Assessment
There can be a wide-spectrum of presentations of acuity.
An A to E assessment may be needed in some cases, with liver failure presenting as a severe multisystem disease, much like septic shock.
Much of the time the presentation will be much less acute, allowing a detailed history and examination.
Key factors in the history include:
An A to E assessment may be needed in some cases, with liver failure presenting as a severe multisystem disease, much like septic shock.
Much of the time the presentation will be much less acute, allowing a detailed history and examination.
Key factors in the history include:
- Relevant past medical history
- Drug history
- Prescribed
- Recreational, including alcohol and IVDU
- Toxin ingestion
- Prescribed
- Foreign travel
- Family history of related conditions
Examination
Key features include:
- Mental state changes - see encephalopathy assessment
- Abdominal examination
- Ascites
- Hepatomegaly
- Splenomegaly
- CVS
- Hyperdynamic circulation
- Jaundice - including scleral examination
- Neurology
- Asterixis
- Apraxia
- Ataxia
- Tremor
Encephalopathy
This is a key feature of liver failure, and the clinical features can be considered as involving:
Encephalopathy grading (West Haven Criteria):
Grade 0 describes subclinical hepatic encephalopathy which may involve some deficits detectable on detailed psychometric testing e.g. memory and coordination changes.
This is a good video on hepatic encephalopathy: https://www.youtube.com/watch?v=sTKg0UmNeeQ
- Level of alertness/consciousness
- Intellectual function
- Personality and behaviour
- Neuromuscular
Encephalopathy grading (West Haven Criteria):
- Change in behaviour, minimal change in conscious level:
- mild confusion,
- change in sleep-wake cycle
- Decreased attention
- Slowed performance of tasks e.g. arithmetic
- mild confusion,
- Gross deficits of mental tasks, some conscious level changes:
- disorientation,
- lethargy
- inappropriate behaviour
- disorientation,
- Notable impact on conscious level, severe impact on cognitive tasks
- Marked confusion,
- incoherent speech,
- sleeping most of the time but arousable to vocal stimuli
- Marked confusion,
- Comatose, unrousable to pain, decorticate or decerebrate posturing
Grade 0 describes subclinical hepatic encephalopathy which may involve some deficits detectable on detailed psychometric testing e.g. memory and coordination changes.
This is a good video on hepatic encephalopathy: https://www.youtube.com/watch?v=sTKg0UmNeeQ
Additional complications include:
The pathophysiology of ALF can lead to CVS changes due to the impact on vasoactive mediators.
This can lead to a high output shock with a vasodilation picture.
Impaired synthesis of clotting factors is a key feature of ALF.
However, this affects both pro and anti-coagulant factors, so the rate of spontaneous bleeding is described as low.
ALF is an immunocompromised state.
Extra care is needed in infection control measures and increased vigilance for infective causes of deterioration.
- Haemodynamic changes
- Coagulopathy
- AKI
- Infection
The pathophysiology of ALF can lead to CVS changes due to the impact on vasoactive mediators.
This can lead to a high output shock with a vasodilation picture.
Impaired synthesis of clotting factors is a key feature of ALF.
However, this affects both pro and anti-coagulant factors, so the rate of spontaneous bleeding is described as low.
ALF is an immunocompromised state.
Extra care is needed in infection control measures and increased vigilance for infective causes of deterioration.
Investigations
Bloods
Imaging
Head imaging may be used in cases of altered neurological state to assess for alternative diagnoses as well as having the potential to demonstrate cerebral oedema.
EEG can demonstrate encephalopathy.
A liver biopsy may be indicated in some cases where the aetiology is unclear.
This is rarely performed in ALF due to the high risk of bleeding, although the transjugular route may reduce this risk.
The results of biopsy may also not be helpful due to a tendency for patchy and non-specific changes.
- Markers of injury
- ALT
- Alk phos (may be raised less or normal)
- ALT
- Markers of impaired function
- Coagulation
- Bilirubin
- Glucose
- Ammonia
- Coagulation
- Infective markers
- Hepatitides
- HIV
- Other viral - CMV, HSV
- Hepatitides
- Immunology
- ANA
- AMA
- Smooth muscle antibody
- Eosiniphillia may be present in drug reactions
- ANA
- Toxicology
- Paracetamol levels
- Blood alcohol
- MDMA
- Paracetamol levels
- Copper studies
Imaging
- CT +/- contrast
- US with portal vein doppler
Head imaging may be used in cases of altered neurological state to assess for alternative diagnoses as well as having the potential to demonstrate cerebral oedema.
EEG can demonstrate encephalopathy.
A liver biopsy may be indicated in some cases where the aetiology is unclear.
This is rarely performed in ALF due to the high risk of bleeding, although the transjugular route may reduce this risk.
The results of biopsy may also not be helpful due to a tendency for patchy and non-specific changes.
Management
Management of these patients can be challenging and involvement of specialist centres may be needed.
The key components of care can be considered as:
The key components of care can be considered as:
- Supportive care
- Specific treatments
- Transplant
Supportive
Supportive care is an essential part of the management of all patients.
Much of this will overlap with general supportive care principles.
Key components specific to ALF include:
Reducing ammonia production is a key part in reducing the encephalopathy.
The components may include:
The lower luminal pH results in more shift to NH4+ form rather than NH3, which due to its ionised state is less absorbable.
There may also be effects of speeding gut transit and changes to the gut flora.
Raised ICP is a potential complication of ALF.
Supportive strategies are mostly the same as for ICP generally.
Efforts are also employed to reduce production of ammonia as above.
Renal replacement therapy may also be employed to reduce ammonia levels, and thereby cerebral oedema.
ICP monitoring is challenging due to the increased risk of bleeding in these patients.
Routine correction of coagulopathy is not recommended, partly due to the mixed clotting abnormalities described, and partly because of the potential impact on transplant assessment (the INR is a key feature).
It is generally only performed to provide cover for high risk interventions.
Ensuring vitamin K deficiency is not present is important, but more of a problem in patients with chronic liver disease.
The concept of reducing protein intake has been described to reduce hepatic encephalopathy as part of reducing ammonia production.
However, this is not well supported, and the consequences of impaired nutrition would seem to outweigh this.
This is more relevant for patients with chronic disease, but still an important consideration.
Much of this will overlap with general supportive care principles.
Key components specific to ALF include:
- Reducing ammonia production
- Managing raised ICP
- Managing coagulopathy
- Nutrition
Reducing ammonia production is a key part in reducing the encephalopathy.
The components may include:
- Lactulose
- Oral rifaximin
The lower luminal pH results in more shift to NH4+ form rather than NH3, which due to its ionised state is less absorbable.
There may also be effects of speeding gut transit and changes to the gut flora.
Raised ICP is a potential complication of ALF.
Supportive strategies are mostly the same as for ICP generally.
Efforts are also employed to reduce production of ammonia as above.
Renal replacement therapy may also be employed to reduce ammonia levels, and thereby cerebral oedema.
ICP monitoring is challenging due to the increased risk of bleeding in these patients.
Routine correction of coagulopathy is not recommended, partly due to the mixed clotting abnormalities described, and partly because of the potential impact on transplant assessment (the INR is a key feature).
It is generally only performed to provide cover for high risk interventions.
Ensuring vitamin K deficiency is not present is important, but more of a problem in patients with chronic liver disease.
The concept of reducing protein intake has been described to reduce hepatic encephalopathy as part of reducing ammonia production.
However, this is not well supported, and the consequences of impaired nutrition would seem to outweigh this.
This is more relevant for patients with chronic disease, but still an important consideration.
Specific Care
There are some potential specific treatment options that may be possible in some disease processes e.g. paracetamol overdose with N-acetylcysteine.
Removing the precipitant is a key feature of managing drug induced disease.
Removing the precipitant is a key feature of managing drug induced disease.
Transplant
This may be the required treatment for some patients.
This is not a universally available option, nor a small undertaking.
A useful question is - “Is the chance of them dying in the next year from this liver failure, higher than the chance of them dying from a liver transplant”.
There is a fairly well established risk assessment tool in the King’s College Hospital Criteria (a.k.a. O’Grady criteria).
The assessment is different between paracetamol OD and other aetiologies.
This is the tool used in paracetamol overdose: https://www.mdcalc.com/kings-college-criteria-acetaminophen-toxicity
Contraindications include:
This is not a universally available option, nor a small undertaking.
A useful question is - “Is the chance of them dying in the next year from this liver failure, higher than the chance of them dying from a liver transplant”.
There is a fairly well established risk assessment tool in the King’s College Hospital Criteria (a.k.a. O’Grady criteria).
The assessment is different between paracetamol OD and other aetiologies.
This is the tool used in paracetamol overdose: https://www.mdcalc.com/kings-college-criteria-acetaminophen-toxicity
Contraindications include:
- Severe cerebral oedema
- Uncontrolled sepsis
- Major psychiatric comorbidity
- Rising vasopressor requirements
Hepatic Encephalopathy
This is a key part of the problem of liver failure, both acutely and chronically.
A key differentiation is between that with normal ICP and that with raised ICP.
As a simple summary, acute liver failure is more likely to result in raised ICP, as there is less time for compensatory changes to occur.
A key part of the pathophysiology is the accumulation of ammonia (NH3)
This is produced in the gut primarily through bacterial metabolic action.
Normally it is well metabolised by the liver and converted to urea through the urea cycle.
In liver failure, this process does not occur to the same degree, and there can be shunting around the liver e.g. when there is portal hypertension.
In the brain this causes a metabolic shift in the brain with increased glutamate production and reduced ATP production.
There is also increase production of glutamine which has an effect on cellular oncotic pressure, leading to oedema, as well as oxidative stress.
However, plasma ammonia levels don’t correlate perfectly with encephalopathy, and other factors appear to be contributory, including:
A key differentiation is between that with normal ICP and that with raised ICP.
As a simple summary, acute liver failure is more likely to result in raised ICP, as there is less time for compensatory changes to occur.
A key part of the pathophysiology is the accumulation of ammonia (NH3)
This is produced in the gut primarily through bacterial metabolic action.
Normally it is well metabolised by the liver and converted to urea through the urea cycle.
In liver failure, this process does not occur to the same degree, and there can be shunting around the liver e.g. when there is portal hypertension.
In the brain this causes a metabolic shift in the brain with increased glutamate production and reduced ATP production.
There is also increase production of glutamine which has an effect on cellular oncotic pressure, leading to oedema, as well as oxidative stress.
However, plasma ammonia levels don’t correlate perfectly with encephalopathy, and other factors appear to be contributory, including:
- Alteration of levels of other neurotransmitters
- Increased inflammatory mediators
- Impairment of blood brain barrier
Links & References
- Nickson, C. Liver failure definitions and scoring systems. LITFL. 2019. https://litfl.com/liver-failure-definitions-and-scoring-systems/
- MDCALC. Hepatic encephalopathy grades/stages. https://www.mdcalc.com/kings-college-criteria-acetaminophen-toxicity
- Strong Medicine. Hepatic encephalopathy.Youtube. 2018. https://www.youtube.com/watch?v=sTKg0UmNeeQ
- Willacy, H. Liver failure. Patient.info. 2019. https://patient.info/doctor/liver-failure
- Tisy, C. Hepatic encephalopathy. Patient.info. 2016. https://patient.info/doctor/hepatic-encephalopathy
- MDCALC. King’s College criteria for acetaminophen toxicity. https://www.mdcalc.com/kings-college-criteria-acetaminophen-toxicity
