Tests
1st tests to order
liver function tests
Test
Hyperbilirubinemia is associated with jaundice, a defining feature of ALF.[1][2][3][4][6] Elevations in liver enzymes are variable depending on etiology. Clinically significant drug-induced liver injury (DILI) is defined:[29] A serum AST or ALT >5 times the upper limit of normal (ULN), or alkaline phosphatase >2 times the ULN (if the baseline is abnormal, use the pretreatment baseline); or a total serum bilirubin >2.5 mg/dL plus an elevated AST, ALT, or alkaline phosphatase level; or an INR >1.5 with an elevated level of AST, ALT, or alkaline phosphatase. Acetaminophen hepatotoxicity is associated with very high aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Further categorization of idiosyncratic DILI is possible using the R value at presentation (R = [ALT/ULN]/[ALP/ULN]). R ≥5 represents a hepatocellular injury profile, 2 < R < 5 represents a mixed injury profile, and R ≤2 represents a cholestatic injury profile.[29] An R value >5 has a 90% sensitivity for ALF.[71]
Wilson disease typically presents with an alkaline phosphatase:bilirubin ratio of <4 and AST:ALT ratio >2.2.[42] In one prospective cohort, these combined laboratory features had a sensitivity and specificity of 100% in the diagnosis of ALF secondary to Wilson disease.[72]
Result
hyperbilirubinemia, elevated liver enzymes
prothrombin time/INR
basic metabolic panel
Test
Renal failure is a known complication of ALF and is predictive of mortality, particularly in acetaminophen overdose.[64] Metabolic derangements in potassium, phosphate, and magnesium are common and should be corrected promptly.
Result
elevated BUN and creatinine, metabolic derangements
CBC
Test
The presence of leukocytosis may suggest infection. Anemia may be present in some patients, particularly in the setting of ALF associated with Wilson disease in which Coombs-negative hemolytic anemia may occur.[42] Thrombocytopenia may suggest preexisting advanced liver disease. A decline in platelets within 7 days of presentation may be associated with onset of systemic inflammatory response syndrome and risk of multiorgan system failure.[73]
Result
leukocytosis, anemia, thrombocytopenia
blood type and screen
Test
Done pre-emptively in case a blood transfusion is required.
Result
specific blood profile of patient
serum amylase and lipase
Test
Serum amylase and lipase levels should be assessed to exclude pancreatitis, which may develop as a complication of ALF; however, hyperamylasemia may also develop as a result of renal dysfunction and multiorgan failure.[51][52][53][54][55] Although hyperamylasemia is associated with an increased risk of mortality, it is not an independent predictor of mortality in ALF.[55]
Result
normal or elevated
arterial blood gas
Test
The presence of acidosis is an important prognostic indicator, particularly in acetaminophen overdose.[64]
Result
metabolic acidosis
arterial blood lactate
Test
Important prognostic indicator in acetaminophen-associated ALF, in which levels >3.5 mmol/L on presentation and >3.0 mmol/L following fluid resuscitation are predictive of mortality. The addition of arterial blood lactate to the King's College Criteria may improve sensitivity in the prediction of mortality associated with acetaminophen-induced ALF.[74]
Result
elevated
acetaminophen level
urine toxicology screen
Test
May be helpful to determine acetaminophen levels in urine following an acetaminophen overdose.
Result
may be positive for acetaminophen
viral hepatitis serologies
Test
Include antihepatitis A immunoglobulin (Ig)M, antihepatitis B core IgM, hepatitis B surface antigen, antihepatitis C IgG, and antihepatitis E IgM. Helpful in exploring potential etiologies of ALF and may guide management, particularly in acute hepatitis B in which antiviral therapy may be initiated.
Result
may be positive
autoimmune hepatitis markers
Test
Serological markers including antinuclear antibody, anti-smooth-muscle antibody, and quantitative immunoglobulins can help to establish this diagnosis and guide further management.
Result
may be positive
pregnancy test
Test
A serum beta-human chorionic gonadotropin (hCG) should be obtained in all females of childbearing age presenting with ALF.[4] Acute viral hepatitis, acute fatty liver of pregnancy, and the hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome may occur during pregnancy.
Result
may be positive
chest x-ray
Test
To assess for signs of aspiration pneumonia (many patients present obtunded with hepatic encephalopathy), pulmonary edema, or other abnormalities that require further evaluation or treatment.
Result
possible aspiration pneumonia
abdominal ultrasound with Doppler
Test
Liver imaging is appropriate if drug-induced liver injury is suspected to assess whether there may be a competing etiology. Abdominal ultrasound is used first to assess whether cirrhosis, biliary obstruction or other focal liver changes are present.[29] An abdominal Doppler study may assess vessel patency and evidence of hepatic vein thrombosis associated with Budd-Chiari syndrome.[4] Abdominal sonography may reveal hepatic surface nodularity suspicious for preexisting cirrhosis; however, this finding may actually reflect acute large-scale necrosis and parenchymal collapse with foci of regenerative nodules rather than chronic changes associated with chronic liver disease.[75]
Result
may show cirrhosis or signs of biliary obstruction; hepatic vessel thrombosis, loss of hepatic venous signal and reverse flow in the portal vein in Budd-Chiari syndrome; hepatomegaly, splenomegaly, hepatic surface nodularity
Tests to consider
factor V level
Test
A low result in the presence of hepatic encephalopathy may be predictive of mortality, particularly in patients with ALF secondary to viral hepatitis.[62] In one prospective cohort of patients with ALF, it was noted that optimal factor V thresholds predictive of survival were >10.5% of normal in acetaminophen ALF and >22% of normal in non-acetaminophen ALF.[63]
Result
low (<20% to 30% of normal)
viral hepatitis polymerase chain reaction (PCR) studies
Test
Include hepatitis B virus DNA, herpes simplex virus DNA, and hepatitis C virus RNA. May assist in establishing the diagnosis, particularly in the acute setting, when serologies may be negative. Obtaining additional viral serologies or PCR studies for Epstein-Barr virus, cytomegalovirus, Varicella zoster, and adenovirus may also be considered as these can be associated with ALF.
Result
may be positive when serology is negative
serum ceruloplasmin
Test
Probably low in ALF secondary to Wilson disease; however, this is a nonspecific finding. If Wilson disease is suspected, further workup should include an assessment for alkaline phosphatase:total bilirubin ratio <4, aspartate aminotransferase:alanine aminotransferase ratio >2.2, serum copper level, 24-hour urine collection for quantitative copper, slit-lamp ophthalmologic evaluation for the presence of Kayser-Fleischer rings, and hepatic copper levels if a liver biopsy is performed.[42][72]
Result
low (<5 mg/dL) in Wilson disease
serum copper
Test
If Wilson disease is suspected, further workup should include an assessment for alkaline phosphatase:total bilirubin ratio <4, aspartate aminotransferase:alanine aminotransferase ratio >2.2, ceruloplasmin, 24-hour urine collection for quantitative copper, slit-lamp ophthalmologic evaluation for the presence of Kayser-Fleischer rings, and hepatic copper levels if a liver biopsy is performed.[42][72] In ALF secondary to Wilson disease, serum copper is markedly elevated (usually >200 micrograms/dL) due to sudden massive hepatic necrosis caused by the release of copper from disrupted hepatocytes. This is typically much higher than in ALF due to other etiologies.[42]
Result
elevated (>200 micrograms/dL) in ALF due to Wilson disease
24-hour urinary copper excretion
Test
Usually very elevated in the setting of ALF secondary to Wilson disease, with levels >125 micrograms over 24 hours. If Wilson disease is suspected, further workup should include an assessment for alkaline phosphatase:total bilirubin ratio <4, aspartate aminotransferase:alanine aminotransferase ratio >2.2, ceruloplasmin, serum copper level, slit-lamp ophthalmologic evaluation for the presence of Kayser-Fleischer rings, and hepatic copper levels if a liver biopsy is performed.[42][72]
Result
elevated (>100 micrograms/24 hours) in Wilson disease
slit-lamp ophthalmologic examination
Test
If Wilson disease is suspected, a slit-lamp evaluation for the presence of Kayser-Fleischer rings may be performed. However, this finding may be absent in 50% of patients with Wilson disease. Further workup may include an assessment for alkaline phosphatase:total bilirubin ratio <4, aspartate aminotransferase:alanine aminotransferase ratio >2.2, ceruloplasmin, serum copper level, 24-hour urine collection for quantitative copper, and hepatic copper levels if a liver biopsy is performed.[42][72]
Result
positive (Kayser-Fleischer rings present) in Wilson disease
arterial ammonia
Test
Characteristically elevated if hepatic encephalopathy is present. This may be useful when differentiating between other causes of altered mental status; however, it is a nonspecific test. High ammonia levels to >200 micromol/L are more specific and may predict an increased risk of developing intracranial hypertension.[76]
Result
elevated
HIV test
Test
Risk of ALF is increased in patients with HIV and hepatitis C coinfection.
Result
may be positive
urinalysis and urine sodium
Test
Should be obtained if renal dysfunction is present. Etiologies of renal failure in ALF may include hypovolemia, acute tubular necrosis, and hepatorenal syndrome.
Result
proteinuria, sediment, low urine sodium (<10 mEq/L)
surveillance cultures
Test
Blood, urine, and sputum cultures should be obtained at regular intervals once advanced grade of encephalopathy develops.
Result
may be positive
Coombs test
Test
If hemolysis is present, a Coombs test may further differentiate between Wilson disease, which is associated with a Coombs-negative hemolysis, versus autoimmune hemolysis, which is typically Coombs-positive.[42]
Result
positive or negative
biomarkers
Test
Testing for biomarkers of alcohol consumption - urinary ethyl glucuronide or serum phosphatidyl ethanol - may be helpful in ruling out alcohol-related liver disease.[4]
Result
elevated in alcohol-related liver disease
liver biopsy
Test
The transjugular approach is preferred given the potential bleeding risk associated with coagulopathy during ALF.[4] In addition to a general histopathologic evaluation, attention should be given to assess for the presence of viral inclusions that may suggest acute herpes simplex hepatitis, hepatic copper levels if Wilson disease is suspected, and for features suggestive of autoimmune hepatitis. Liver biopsies are rarely performed in the setting of ALF because they are not required to confirm a diagnosis and generally do not have an impact on clinical management or prognosis. However, if a drug-induced liver injury is suspected, liver biopsy may help to identify the hepatotoxic drug, based on the histologic pattern(s), or determine the mechanism of injury, and it may also provide useful prognostic information.[29] Biopsy may be considered to exclude malignancy or infiltrative disease, or to diagnose autoimmune hepatitis.[4]
Result
hepatocellular necrosis, microvesicular steatosis, viral inclusions, elevated hepatic copper
CT scan of head
Test
Should be considered once grade 3 to 4 hepatic encephalopathy develops to assess for presence of cerebral edema or other underlying pathology.
Result
cerebral edema, hemorrhage
CT/MR cholangiography
Test
CT and MR cholangiography may be useful in cases of suspected drug-induced liver injury to assess whether vascular abnormalities or pancreatobiliary disease are present.[29][77]
Result
normal or evidence of concomitant pancreatobiliary disease; sclerosing cholangitis-like changes have been described in a minority of patients with drug-induced liver injury
Transcranial Doppler
Test
A transcranial Doppler, with estimation of cerebral perfusion pressure and intracranial pressure (ICP), may be considered in patients with grade 3 to 4 hepatic encephalopathy who are at risk of intracranial hypertension or for those in whom developing cerebral edema is expected.[57]
Result
estimated ICP >20 mmHg may indicate intracranial hypertension
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