Drug-induced liver injury (DILI) is the primary cause of ALF in the United States of America (USA), Europe, and Australia, while acute hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis E virus (HEV) are the primary causes in Asia and Africa ^[1][2][4,5]. Acetaminophen is the most common medication associated with ALF and is responsible for 45.7% of ALF cases in North America, and 65.4% in the UK ^[3][6]. In Europe, it is reported that 8% of all liver transplantations (LT) are performed due to ALF, and of those ALF cases, 19% are caused by viral hepatitis, 18% by DILI, 4% have toxic causes, 3% have traumatic or post-operative ALF, while 56% have unknown or other causes ^[4][7]. In India, viral hepatitis (HAV, HBV, HEV) is the primary cause of ALF, followed by DILI, mainly due to antituberculosis drugs ^[5][6][8,9]. In China, traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs have been identified as the leading causes of DILI ^[7][10].

Liver injury caused by acetaminophen overdose is usually characterized by extreme hepatocellular pattern liver transaminase elevations with normal or slightly increased bilirubin levels within 8–12 h of excess acetaminophen intake, and often progresses rapidly to multiorgan failure and coma. Multiorgan failure with acetaminophen overdose is due to an initial massive proinflammatory response causing systemic inflammatory response syndrome (SIRS) and a compensatory anti-inflammatory response leading to immune cell dysfunction ^[8][11]. Lactic acidosis, acute kidney injury (AKI), hypoglycemia, and hypophosphatemia can also be seen in patients with ALF due to acetaminophen overdose. Severe metabolic acidosis may require renal replacement therapy (RRT) in certain patients. Other causes of metabolic acidosis such as salicylates, tricyclic antidepressants, or methanol overdose should also be investigated.

Less than 1% of the patients with HAV infection develop ALF, and ALF is mainly seen in elderly patients, who generally have a worse prognosis. Overall, ALF due to HAV has a good prognosis with 70% spontaneous or transplant-free survival (4). HBV is the most common viral cause of severe ALF due to either de novo infection, reactivation in a patient with previous HBV infection, or delta superinfection ^[9][3]. Less than 4% of patients with acute HBV develop ALF. Mortality rates for ALF due to HBV are higher than for ALF due to HAV or HEV infections. Acute hepatitis C virus (HCV) infection very rarely progresses to ALF. Herpes simplex virus 1 and 2 (HSV1, HSV2) and varicella-zoster virus (VZV) are rare causes of ALF, and are more commonly seen in immunosuppressed patients; however, ALF may occur in immunocompetent patients. Epstein–Barr virus (EBV) and cytomegalovirus (CMV) nucleic acid tests should be performed in patients with no clear etiology. Skin or mucous membrane vesicles may be seen with HSV.

In the USA and Europe, approximately 8% of all cases of ALF are due to HBV. About two-thirds of ALF cases due to HBV are because of new infections and the remainder are due to reactivation of HBV in the setting of unrecognized chronic HBV infection or in the setting of immunosuppression, such as chemotherapy or immune modulators ^[1][4]. ALF due to reactivation of HBV usually has a worse prognosis than that caused by de novo HBV infection. Acute HEV is mostly seen in patients with a travel history to endemic areas, such as Asia and parts of Africa, although very rarely it can be seen in Europe and in the USA. Mortality rates for ALF due to HEV are low; however, worse outcomes have been reported in elderly patients, those with preexisting chronic liver disease, and pregnant women.

ALF due to non-acetaminophen DILI often presents with less severe transaminase elevations and higher bilirubin levels compared to acetaminophen, and multiorgan failure is less common. The most common causes of non-acetaminophen toxicity are antituberculosis drugs (mainly isoniazid), antimicrobials (nitrofurantoin and ketoconazole), antiepileptics (valproic acid, phenytoin), and non-steroidal anti-inflammatory drugs (NSAIDs) ^[9][3]. Non-acetaminophen DILI is usually seen within six months of drug initiation and often presents with lower aminotransferase levels but higher bilirubin concentrations compared to acetaminophen or ischemic hepatitis. Idiosyncratic drug reactions are rare and not dose-dependent. If non-acetaminophen DILI progresses to ALF, which occurs in approximately 10% of patients, up to 70–80% of the latter need emergent LT or die ^[10][11][12,13]. Mushroom poisoning, mainly with amanita phalloides and related species, usually presents with severe abdominal pain, nausea, vomiting, and diarrhea within hours to one day of ingestion and acute renal failure usually precedes ALF ^[12][14].

If any other autoimmune disease is present, suspicion for autoimmune hepatitis (AIH) as the cause of ALF should be considered. Approximately 80% of patients with ALF due to AIH are women and ALF due to AIH has particularly poor outcomes and often requires LT ^[1][13][4,15]. Patients with AIH often have elevated IgG levels, positive anti-smooth muscle antibody (ASMA), antinuclear antigen (ANA), liver–kidney microsomal antibody (LKM), or any combination of these. It should be noted that those antibodies can be negative in the setting of ALF due to AIH, and their absence does not rule out AIH. In addition, mildly positive antibodies can also be present in other conditions causing ALF. Liver biopsy may help in the diagnosis of ALF due to AIH; however, it often lacks the typical AIH findings of portal inflammation with plasma-cell-rich infiltrate and interface hepatitis, but rather shows centrilobular hemorrhagic necrosis preceding chronic portal inflammation ^[9][3]. With the progression of ALF, necrosis can become confluent, making the histological diagnosis challenging.

In ALF due to Wilson disease, most patients are <20 years of age, and it presents with Coombs-negative hemolytic anemia and high bilirubin to ALP ratio. ALP is usually normal or very low. Approximately half of the patients have Kayser–Fleischer rings; however, it may be difficult to assess this finding in patients with HE. In addition, most patients also rapidly progress to renal failure and have low serum uric acid levels. Serum ceruloplasmin can be very low but can also be normal or increased in ALF. Falsely normal serum ceruloplasmin can be seen in Wilson disease as it is an acute phase reactant. In addition, serum ceruloplasmin can also be low in cases of ALF due to other causes. Serum and urinary copper are increased; however, their values are not reliable in the setting of chronic liver disease. Twenty-four-hour urine copper excretion may also be unreliable in the setting of kidney dysfunction and low urine output. Liver biopsy to estimate liver copper is also not reliable in the setting of ALF, in particular in the setting of cholestasis. Genetic studies of ATP7B testing results are often not available on short notice at most centers. Patients with ALF due to Wilson disease rarely recover without transplantation.

Pregnancy-related ALF occurs in the third trimester in the form of hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, or acute fatty liver of the pregnancy (AFLP) ^[14][16]. AFLP is characterized by diffuse hepatic steatosis, low transaminase levels, hypoglycemia, and increased urate levels, and has a 20% mortality rate. Immediate delivery of the fetus is needed in both HELLP syndrome and AFLP, and emergent LT is rarely needed.

ALF after hemi-hepatectomy can be seen after an extensive resection of the liver. Spontaneous recovery is usually seen if there is no preexisting chronic liver disease. The AST/ALT ratio is usually >1 in Budd–Chiari syndrome, and it is most commonly seen in women in their fourth or fifth decades and is associated with hypercoagulable states ^[15][17]. Anticoagulation should be initiated as soon as a diagnosis is made and transjugular intrahepatic portosystemic shunt (TIPS) is the preferred intervention for decompression in parallel with LT listing if there is no response to therapeutic interventions ^[16][2]. Survival rates have been reported as 37–40%, despite LT. Secondary causes of ALF may include sepsis, malaria, leptospirosis, rickettsial disease, thyroid disease, Still’s disease, and hemophagocytic syndromes ^[9][17][3,18]. Despite extensive investigation in many patients, the cause of ALF remains unknown ^[2][5]. Common causes of ALF are shown in Table 1, and a special pattern of liver injury is shown in Table 2.

Many symptoms of ALF are unspecific and may include fatigue, lethargy, confusion, generalized weakness, nausea, right upper quadrant pain, jaundice, and pruritus. Physical examination findings may reveal right upper quadrant tenderness, hepatomegaly, ascites, and vesicular skin lesions with HSV infection. Symptoms of cognitive dysfunction may not be overt on presentation. Laboratory test abnormalities often include elevated liver tests (often markedly elevated), and elevated bilirubin level. INR ≥ 1.5 is part of the ALF definition and must be present. Other laboratory findings, such as hemolytic anemia, elevated serum creatine and blood urea nitrogen, hypoglycemia, hypophosphatemia, hypomagnesemia, elevated amylase and lipase, elevated ammonia level, and elevated lactate dehydrogenase, are often present. Decreasing aminotransferase levels may indicate recovery but may also suggest worsening liver failure due to loss of hepatocyte mass. For coagulation evaluation, viscoelastic testing with rotational thromboelastography or rotational thromboelastometry should be used and is recommended over INR in critically ill patients by the Society of Critical Care Medicine, as INR reflects the extent of liver injury rather than determining coagulopathy ^[18][19]. Arterial ammonia levels have been shown to have a direct correlation with the prognosis of ALF.

Identifying the etiology is important to guide the treatment and to provide prognostic information. A comprehensive medical history, with a particular emphasis on medications, and herbal and nutritional supplements, within the past six months should be performed. Urine and serum toxicology screenings, urinary ethyl glucuronide, or serum phosphatidyl ethanol should be obtained if alcohol-related liver disease is suspected. If the history, laboratory workup, and imaging findings do not provide any specific etiology for ALF, a liver biopsy might be needed; however, the risks associated with bleeding and death must be accounted for ^[9][3]. A routine liver biopsy is not recommended, and if needed, a transjugular liver biopsy is preferred as opposed to a percutaneous liver biopsy. Differentiating severe acute hepatitis from ALF mainly depends on the presence of HE. Patients with severe acute hepatitis may have INR > 1.5 but not have HE.

Differentials of very high transaminase levels (>3000 IU/L) and total bilirubin <5.0 mg/dL include mainly ischemic hepatic injury and acetaminophen (or less likely heat stroke or cocaine toxicity). Poor perfusion causing ischemic hepatic injury can be due to hypotension due to shock of any cause, heart failure, hypoxia, pulmonary failure, major surgery, trauma, and cocaine use. Neurologic Wilson disease usually includes dysarthria, dystonia, tremors, and Parkinsonism as opposed to HE secondary to ALF due to Wilson disease.

ALF can be further categorized as hyperacute, acute, and subacute based on the onset of encephalopathy according to the O’Grady classification ^[16][2]. Time frames are defined as <7 days for hyperacute ALF, 7–21 days for acute ALF, and >21 days for subacute ALF. The risk of cerebral edema is highest with hyperacute ALF and lowest with subacute ALF; however, the risk of death is inverse, being lowest with hyperacute ALF and highest with subacute ALF ^[16][2].

4. Imaging Findings

Abdominal Doppler ultrasonography should be obtained to evaluate for Budd–Chiari syndrome, portal hypertension, hepatic steatosis, hepatic congestion, and underlying cirrhosis. Cirrhosis may be present in patients with ALF due to Wilson disease, vertically transmitted HBV, AIH, and imaging may reveal nodular and heterogenous appearance of cirrhosis. Imaging may also reveal splenomegaly and ascites, which may be due to liver cirrhosis. It should be noted that a massively necrotic liver due to ALF may also look nodular and does not necessarily indicate cirrhosis. Pulmonary vascular congestion may be present in up to 30% of the patients with ALF on chest radiography. Neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI) may reveal cerebral edema; however, CT is not sensitive in the early stages.