Aetiology
Identifying the cause of ALF is important to guide treatment and determine prognosis.
Aetiology varies significantly between different parts of the world. In the UK and the US, paracetamol overdose is the most common aetiology of ALF. Analysis of 2614 adult patients prospectively enrolled in the US Acute Liver Failure Study Group (ALFSG) between 1998 and 2019 showed that paracetamol hepatotoxicity accounts for approximately 46% of all cases.[13] Paracetamol overdose accounts for nearly 66% of ALF cases in the UK.[14] Paracetamol overdose appears to be equally divided between intentional and unintentional cases.[15]
Other causes of ALF include idiosyncratic drug-induced liver injury (11%), acute hepatitis B (7%), autoimmune hepatitis (7%), ischaemic hepatitis (7%), and acute hepatitis A (1%). Up to 12% of cases remain indeterminate.[13]
Altogether, over half of all ALF cases are associated with a drug-induced reaction. After paracetamol, antimicrobials are the most commonly implicated drugs.[16] One study suggests that paracetamol may potentially contribute to, or be a causal factor in, many cases that are otherwise indeterminate.[17] In cases of non-paracetamol drug-induced liver injury, a rise in ALF resulting from herbal and dietary supplements has been noted.[18] Anti-infective agents, herbal and dietary supplements, and non-steroidal anti-inflammatory drugs remain major categories of agents associated with drug-induced ALF.[16]
One multicentre retrospective analysis conducted in Sweden (279 patients) showed a similar distribution of ALF aetiology for paracetamol toxicity-induced ALF (42%) and other drug-induced ALF (15%).[19] However, a smaller retrospective study conducted in Germany (102 patients) revealed a different distribution of ALF aetiologies with indeterminate cause for 21% of the cases, followed by acute hepatitis B (18%), paracetamol (16%), and Budd-Chiari syndrome (9%).[20] Although the retrospective studies from Sweden and Germany are insightful, the key advantage of the data reported from the ALFSG was the prospective design and size of the study compared with the Swedish and German cohorts. This adds to the validity of the findings from the ALFSG, although it is clear that aetiology may also depend on geography.
Globally, viral infection accounts for the majority of cases of ALF.[21] Hepatitis E virus accounts for 75% of cases in Bangladesh and 44% of cases in India. In Japan, 42% of cases are caused by hepatitis B virus (HBV). HBV accounts for 22% of cases in Sudan. Paracetamol overdose is very rare in all of these regions.[9]
Pathophysiology
Although ALF develops as a consequence of many different causal pathways, most cases are characterised by massive hepatocyte necrosis, which may ultimately result in organ failure. On a cellular level, both hepatocyte necrosis and apoptosis may coexist in the setting of ALF.[11] ALF can occur without histological evidence of hepatocellular necrosis; examples of this include acute fatty liver of pregnancy and Reye's syndrome.[22] Efforts to more accurately define factors involved in the pathogenesis of liver injury in the setting of ALF, including hepatocyte apoptosis and regeneration, may lead to the discovery of novel biomarkers that could predict outcomes.[11]
ALF secondary to drug-induced liver injury may occur as an idiosyncratic drug reaction or, as in the case of paracetamol, in a dose-dependent manner.
Paracetamol is predominantly metabolised in the liver through glucuronidation and sulfation, with a small amount metabolised by the cytochrome P450 system. A toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI), generated via the P450 pathway is subsequently conjugated by glutathione. In the setting of paracetamol overdose, glutathione stores may become depleted, resulting in direct hepatocyte injury via NAPQI.[23]
Induction of the P450 system through chronic alcohol use or barbiturates and depletion of glutathione stores in settings such as nutritional deficiency may result in a greater propensity to develop paracetamol hepatotoxicity. Excess alcohol use and fasting have been associated with paracetemol-induced liver injury after taking therapeutic doses of paracetemol.[24]
Classification
By interval from onset of jaundice to development of hepatic encephalopathy[4]
The American College of Gastroenterology classify liver failure as:
Hyperacute if occurring within 7 days
Acute if occurring between 7 and 21 days
Subacute if between 22 days and 26 weeks.
By interval from onset of hepatic illness to development of hepatic encephalopathy[1][2]
Hepatic failure is classified as:
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