History and exam
Key diagnostic factors
common
presence of risk factors
Key risk factors include alcohol abuse, age >40 years, female gender, poor nutritional status, pregnancy, chronic hepatitis B, and the use of multiple paracetamol preparations for chronic pain.
hepatotoxic drugs
Determining whether ALF is associated with paracetamol overdose or other hepatotoxic drugs is important in assessment of prognosis and initiation of aetiology-specific therapies such as acetylcysteine. Enquire about use of herbal and dietary supplements in addition to prescription drugs.[30]
Patients with chronic pain who use multiple analgesics, particularly opioids, are at potentially increased risk of ALF as they may be taking multiple paracetamol-containing preparations.[25] Most cases of paracetamol-induced ALF in the US involve overdose with paracetamol combination products, including paracetamol combined with an opioid and paracetamol combined with diphenhydramine.[66] Although only approximately 10% of drug-induced liver injury cases progress to ALF, this is associated with a poor prognosis, high mortality, and need for liver transplantation in up to 40% of patients.[67]
chronic alcohol misuse
A significant risk factor for the development of ALF. Alcohol use is more commonly associated with unintentional paracetamol overdoses and may be a risk factor for significant hepatotoxicity in patients who present with acetaminophen overdose.[25][26] People who misuse alcohol have been shown to develop ALF following ingestion of lower (therapeutic) doses of paracetamol (≤4 g per day) and have lower serum acetaminophen levels than those who do not misuse.[24][25] In addition, alcohol misuse may be associated with a greater risk of developing ALF in the setting of acute exposure to a hepatitis virus, such as hepatitis B.[27] At least moderate chronic alcohol consumption (≥3 drinks per week) is associated with decreased survival in the setting of both paracetamol and non-paracetamol ALF.[28]
jaundice
coagulopathy
A defining feature of ALF characterised by international normalised ratio (INR) >1.5. Coagulation parameters have prognostic value and may be monitored to assess for ongoing hepatic dysfunction or resolution in ALF. Assessment in all patients is recommended.[4]
In one study of 1000 patients with ALF, coagulopathy was found to be moderate in 81% of patients (INR 1.5 to 5.0), severe in 14% of patients (INR 5.0 to 10.0), and very severe in 5% of patients (INR >10.0).[68]
signs of hepatic encephalopathy
A defining feature of ALF. Hepatic encephalopathy encompasses a spectrum of neurological and psychiatrical symptoms and signs. The time of onset of encephalopathy in relation to jaundice is important in the assessment of prognosis and further characterisation of ALF.[1][2][3][4][6]
Assessment of a patient's level of consciousness, as well as physical examination findings such as asterixis, is essential. Patients may develop motor signs such as hypertonia, hyperreflexia, and a positive Babinski sign. Extrapyramidal signs such as bradykinesia, slow monotonous speech, and dyskinesia are common.[49] The West Haven Criteria may be used to categorise hepatic encephalopathy into grades based on severity.[49][69][70]
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.
Other diagnostic factors
common
absence of history of chronic liver disease
Chronic liver disease may present as an acute exacerbation with the clinical features of ALF. In addition, patients with chronic liver disease may be at increased risk of liver failure secondary to drug toxicities or superinfections with other forms of viral hepatitis.[40][44][45][46] The presence of underlying chronic liver disease precludes the diagnosis of ALF, as ALF is defined by the absence of pre-existing liver disease.
abdominal pain
Common symptom in ALF.
nausea
Common symptom in ALF.
vomiting
Common symptom in ALF.
malaise
Common symptom in ALF.
signs of cerebral oedema
Cerebral oedema is a common complication of ALF with increased frequency in advanced grades of hepatic encephalopathy and hyperacute presentations. Physical examination findings associated with cerebral oedema and intracranial hypertension include abnormal pupillary reflexes, muscular rigidity, and decerebrate posturing in advanced stages.
right upper quadrant tenderness
May be present in ALF.
hepatomegaly
May be present in settings such as acute viral hepatitis, congestive heart failure with hepatic congestion, Budd-Chiari syndrome, and infiltrative malignancies.
absence of splenomegaly
The presence of this finding may suggest chronic liver disease or underlying cirrhosis; however, ascites can occur acutely in rare cases of Budd-Chiari syndrome, as well as in cases of subacute liver failure.[51]
absence of spider angiomata
The presence of this finding may suggest chronic liver disease or underlying cirrhosis.
absence of palmar erythema
The presence of this finding may suggest chronic liver disease or underlying cirrhosis.
absence of ascites
depression or suicidal ideation
In the US, approximately one half of ALF cases secondary to paracetamol overdose are intentional and over half of cases occur in individuals who are taking antidepressant therapy.[25] Patients who have a history of repeated suicide attempts may potentially not be eligible for liver transplant listing.[48]
Methods to restrict access to paracetamol have been used in Europe with significant reductions of hospital admissions, liver transplants, and deaths associated with paracetamol overdose.[71]
uncommon
Wilson's disease
Accounts to approximately 3% of all ALF.[43] ALF due to Wilson's disease is typically associated with non-immune (Coombs‐negative) intravascular haemolysis, coagulopathy unresponsive to parenteral vitamin K administration, progressive encephalopathy, and rapid progression to renal failure. Severe non-immune intravascular haemolysis is an important feature of classic presentation of ALF due to Wilson's disease.[43] ALF due to Wilson's disease has a high mortality rate (80% to 99%) if not treated with liver transplantation.
exposure to hepatotoxins
Exposure to specific hepatotoxins, such as ingestion of Amanita phalloides mushrooms, may require specific management strategies and therapy. Patients present with severe gastroenteritis symptoms 6 to 12 hours after ingestion, with evolving hepatotoxicity within 24 to 36 hours and onset of progressive liver and multi-organ failure within 4 to 7 days.
illicit drug use
Certain populations such as intravenous drug users are at increased risk of exposure to viral hepatitis, such as hepatitis B or C, which may be causal or contribute to a presentation of ALF.
absence of malignancy
Primary hepatobiliary malignancy or liver metastases can present with acute jaundice, liver dysfunction, and altered mentation. However, abdominal imaging will reveal malignancy within the liver.
Risk factors
strong
chronic alcohol misuse
A significant risk factor for the development of ALF. Alcohol use is more commonly associated with unintentional paracetamol overdoses and may be a risk factor for significant hepatotoxicity in patients who present with paracetamol overdose.[25][26] People who misuse alcohol have been shown to develop ALF following ingestion of therapeutic lower doses of paracetamol (≤4 g per day) and have lower serum paracetamol levels than those who do not misuse.[24][25] In addition, alcohol misuse may be associated with a greater risk of developing ALF in the setting of acute exposure to a hepatitis virus, such as hepatitis B.[27] At least moderate chronic alcohol consumption (≥3 drinks per week) is associated with decreased survival in the setting of both paracetamol and non-paracetamol ALF.[28]
poor nutritional status or fasting
Associated with an increased risk of ALF in the setting of paracetamol hepatotoxicity due to depletion of hepatic glutathione stores, and may be a contributing factor to the increased risk of ALF in people who misuse alcohol following paracetamol overdose. Fasting is a risk factor for developing paracetamol-induced liver injury after taking therapeutic doses of paracetamol.[24]
May also be a risk factor for ALF in the setting of acute viral hepatitis.[27]
female sex
pregnancy
The risk of ALF is increased in the setting of acute viral hepatitis and pregnancy, particularly hepatitis E infection.[33][34] Data suggest that hepatitis E may occur more frequently in developed countries than previously thought, and is associated with a significant risk during pregnancy.[35][36] The incidence of hepatitis E infection is increased among pregnant women and is associated with a higher hepatitis E viral load, increased risk of ALF, and increased mortality.[37] The incidence of ALF in pregnant women with acute hepatitis E infection has been reported as high as 69% in some populations.[37]
Acute fatty liver of pregnancy, and the haemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome, occur during pregnancy and may present as ALF.
chronic hepatitis B
Hepatitis B surface antigen carriers are up to 9 times more likely to develop ALF in the setting of acute hepatitis, regardless of aetiology.[38][39]
Individuals with chronic hepatitis B infection are also at risk of developing co-infection with hepatitis D virus, which is associated with a greater frequency of severe hepatitis and ALF compared with hepatitis B alone.[40] Hepatitis B carriers who undergo immunosuppressive or cancer chemotherapy can develop viral re-activation and ALF.[41]
chronic pain and narcotic use
Patients with chronic pain who use multiple analgesics, particularly opioids, are at potentially increased risk of ALF as they may be taking multiple paracetamol-containing preparations.[25]
herbal and dietary supplement hepatotoxicity
Drug-induced liver injury caused by herbal and dietary supplements accounted for 7% of cases of drug-induced liver injury in the US between 2013 and 2020.[18] This represents an eightfold increase in incidence since 1995.[18] ALF resulting from complementary and alternative medicines is associated with higher rates of liver transplantation, and lower transplant-free survival, compared with ALF secondary to prescription drug-induced liver injury.[16][42]
Wilson's disease
Accounts to approximately 3% of all ALF. ALF due to Wilson's disease is typically associated with non-immune (Coombs‐negative) intravascular haemolysis, coagulopathy unresponsive to parenteral vitamin K administration, progressive encephalopathy, and rapid progression to renal failure. Severe non-immune intravascular haemolysis is an important feature of classic presentation of ALF due to Wilson's disease.[43] ALF due to Wilson's disease has a high mortality rate (80% to 99%) if not treated with liver transplantation.
weak
age >40 years
The impact of age on drug-induced liver injury susceptibility is not well established. The increased incidence of drug-induced liver injury with increasing age may partly be explained by greater drug use by older people.[30]
In one prospective cohort of individuals with paracetamol-induced ALF, increased age was shown to be associated with a higher incidence of unintentional paracetamol overdose and ALF in older patients occurred with lower doses of ingested paracetamol (≤4 g per day).[25]
Large retrospective studies have found that age >40 years may be associated with an increased risk of significant hepatotoxicity, ALF, and mortality in patients who present with paracetamol overdose.[26][31]
Prospective studies have also determined that increasing age may be associated with the development of ALF in cohorts presenting with predominantly acute viral hepatitis.[32]
paracetamol and antidepressant therapy
In one prospective series of patients, included in the US Acute Liver Failure Study Group, who developed paracetamol-induced ALF, the majority (61%) of individuals were on antidepressant therapy.[25]
chronic hepatitis C
In one retrospective study of patients presenting with paracetamol overdose, chronic hepatitis C infection was associated with an increased risk of acute liver injury and a more severe disease course, including liver failure.[44]
Patients with chronic hepatitis C appear also to have a significantly greater risk of developing ALF in the setting of acute hepatitis A superinfection compared with patients with chronic hepatitis B.[45]
HIV and hepatitis C co-infection
One large retrospective study found that individuals with HIV infection have an overall greater risk of ALF when they are co-infected with hepatitis C. This risk may be increased as much as fourfold in the setting of highly active antiretroviral therapy, although these cases involve patients with underlying chronic hepatitis C infection and likely pre-existing chronic liver disease.[46]
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