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.
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).
The development of HE is the key differentiating factor between ALF and ALI.
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:
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).
An emergency liver transplantation may be an option for these aetiologies
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.
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.
The severity of HE can be graded using the West Haven criteria:
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.
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.
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).
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.
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.
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).
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.
The European Association for the Study of the Liver (EASL) set out guidance for when to transfer to a liver transplant centre.
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.
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:
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.
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.
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.
We outline some of the broad management principles of patients with ALF based on organ-systems.
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.
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