History and exam

Key diagnostic factors

common

Determining whether ALF is associated with acetaminophen overdose or other hepatotoxic drugs is important in assessment of prognosis and initiation of etiology-specific therapies such as acetylcysteine. Enquire about use of herbal and dietary supplements in addition to prescription drugs.[29]

Patients with chronic pain who use multiple analgesics, particularly opioids, are at potentially increased risk of ALF as they may be taking multiple acetaminophen-containing preparations.[24] Most cases of acetaminophen-induced ALF in the US involve overdose with acetaminophen combination products, including acetaminophen combined with an opioid and acetaminophen combined with diphenhydramine.[65] 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.[66]

A significant risk factor for the development of ALF. Alcohol use is more commonly associated with unintentional acetaminophen overdoses and may be a risk factor for significant hepatotoxicity in patients who present with acetaminophen overdose.[24][25] People who misuse alcohol have been shown to develop ALF following ingestion of lower (therapeutic) doses of acetaminophen (≤4 g per day) and have lower serum acetaminophen levels than those who do not misuse.[23][24] 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.[26] At least moderate chronic alcohol consumption (≥3 drinks per week) is associated with decreased survival in the setting of both acetaminophen and non-acetaminophen ALF.[27]

The risk of ALF is increased in the setting of acute viral hepatitis and pregnancy, particularly hepatitis E infection.[32][33]​​ Data suggest that hepatitis E may occur more frequently in developed countries than previously thought, and is associated with a significant risk during pregnancy.[34][35] 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.[32] The incidence of ALF in pregnant women with acute hepatitis E infection has been reported as high as 69% in some populations.[36]

Acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome, occur during pregnancy and may present as ALF.

A defining feature of ALF. The presence of jaundice and its relation to the onset of hepatic encephalopathy is important in the assessment of prognosis and further characterization of ALF.[1][2][3][4][6]

A defining feature of ALF characterized by international normalized 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).[67]​ Severe forms of coagulopathy may be associated with bleeding, making invasive procedures difficult in such patients.[68]

A defining feature of ALF. Hepatic encephalopathy encompasses a spectrum of neurologic and psychiatric symptoms and signs. The time of onset of encephalopathy in relation to jaundice is important in the assessment of prognosis and further characterization of ALF.[1][2][3][4]​​[6]

Assessment of a patient's level of consciousness, as well as physical exam 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 categorize 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 behavior, dyspraxia, asterixis.

Grade 3: somnolence to semistupor, responsive to vocal stimuli, marked confusion, gross disorientation (disoriented in time and space), bizarre behavior. Physical findings may include hyperreflexia, nystagmus, clonus, and rigidity.

Grade 4: coma.

Other diagnostic factors

common

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.[39][43][44][45] The presence of underlying chronic liver disease precludes the diagnosis of ALF, as ALF is defined by the absence of preexisting liver disease.

Common symptom in ALF.

Common symptom in ALF.

Common symptom in ALF.

Common symptom in ALF.

Cerebral edema is a common complication of ALF with increased frequency in advanced grades of hepatic encephalopathy and hyperacute presentations. Physical exam findings associated with cerebral edema and intracranial hypertension include abnormal pupillary reflexes, muscular rigidity, and decerebrate posturing in advanced stages.

May be present in ALF.

May be present in settings such as acute viral hepatitis, congestive heart failure with hepatic congestion, Budd-Chiari syndrome, and infiltrative malignancies.

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]

The presence of this finding may suggest chronic liver disease or underlying cirrhosis.

The presence of this finding may suggest chronic liver disease or underlying cirrhosis.

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.[4][51]

Approximately one half of ALF cases in the US secondary to acetaminophen overdose are intentional and over half of cases occur in individuals who are taking antidepressant therapy.[24] Patients who have a history of repeated suicide attempts may potentially not be eligible for liver transplant listing.[48]

uncommon

Accounts to approximately 3% of all ALF.[42]​ ALF due to Wilson disease is typically associated with nonimmune (Coombs‐negative) intravascular hemolysis, coagulopathy unresponsive to parenteral vitamin K administration, progressive encephalopathy, and rapid progression to renal failure. Severe nonimmune intravascular hemolysis is an important feature of classic presentation of ALF due to Wilson disease.[42]​​ ALF due to Wilson disease has a high mortality rate (80% to 99%) if not treated with liver transplantation.

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 multiorgan failure within 4 to 7 days.

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.

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

A significant risk factor for the development of ALF. Alcohol use is more commonly associated with unintentional acetaminophen overdoses and may be a risk factor for significant hepatotoxicity in patients who present with acetaminophen overdose.[24][25] People who misuse alcohol have been shown to develop ALF following ingestion of therapeutic lower doses of acetaminophen (≤4 g per day) and have lower serum acetaminophen levels than those who do not misuse.[23][24] 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.[26] At least moderate chronic alcohol consumption (≥3 drinks per week) is associated with decreased survival in the setting of both acetaminophen and non-acetaminophen ALF.[27]

Associated with an increased risk of ALF in the setting of acetaminophen 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 acetaminophen overdose. Fasting is a risk factor for developing acetaminophen-induced liver injury after taking therapeutic doses of acetaminophen.[23]

May also be a risk factor for ALF in the setting of acute viral hepatitis.[26]

Several prospective studies have found that women are more likely to develop ALF, particularly in the setting of drug-induced liver injury.[7][15][28]

The risk of ALF is increased in the setting of acute viral hepatitis and pregnancy, particularly hepatitis E infection.[32][33]​ Data suggest that hepatitis E may occur more frequently in developed countries than previously thought, and is associated with a significant risk during pregnancy.[34][35] 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.[36] The incidence of ALF in pregnant women with acute hepatitis E infection has been reported as high as 69% in some populations.[36]

Acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome, occur during pregnancy and may present as ALF.

Hepatitis B surface antigen carriers are up to 9 times more likely to develop ALF in the setting of acute hepatitis, regardless of etiology.[37][38]

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.[39] Hepatitis B carriers who undergo immunosuppressive or cancer chemotherapy can develop viral reactivation and ALF.[40]

Patients with chronic pain who use multiple analgesics, particularly opioids, are at potentially increased risk of ALF as they may be taking multiple acetaminophen-containing preparations.[24]

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.[17] This represents an eightfold increase in incidence since 1995.[17] 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.[15][41]​​

Accounts to approximately 3% of all ALF. ALF due to Wilson disease is typically associated with nonimmune (Coombs‐negative) intravascular hemolysis, coagulopathy unresponsive to parenteral vitamin K administration, progressive encephalopathy, and rapid progression to renal failure. Severe nonimmune intravascular hemolysis is an important feature of classic presentation of ALF due to Wilson disease.[42]​ ALF due to Wilson disease has a high mortality rate (80% to 99%) if not treated with liver transplantation.

weak

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.[29]

In one prospective cohort of individuals with acetaminophen-induced ALF, increased age was shown to be associated with a higher incidence of unintentional acetaminophen overdose and ALF in older patients occurred with lower doses of ingested acetaminophen (≤4 g per day).[24]

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 acetaminophen overdose.[25][30]

Prospective studies have also determined that increasing age may be associated with the development of ALF in cohorts presenting with predominantly acute viral hepatitis.[31]

In one prospective series of patients included in the US Acute Liver Failure Study Group who developed acetaminophen-induced ALF, the majority (61%) of individuals were on antidepressant therapy.[24]

In one retrospective study of patients presenting with acetaminophen overdose, chronic hepatitis C infection was associated with an increased risk of acute liver injury and a more severe disease course, including liver failure.[43]

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.[44]

One large retrospective study found that individuals with HIV infection have an overall greater risk of ALF when they are coinfected 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 preexisting chronic liver disease.[45]

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