Viral Hepatitis and Liver Disease Website Course

Evaluating Liver Test Abnormalities

Understanding the Pathophysiology of Liver Disease

for Health Care Providers

Marked Aminotransferase Elevation

Abnormal liver test > Hepatocellular pattern > Acute > Marked ALT/AST elevation


The differential diagnosis of marked aminotransferase elevations (more than 15 times the upper limit of normal) is quite limited. This degree of elevation is generally associated with massive hepatocellular injury and/or necrosis. Acute hepatocellular injury (acute hepatitis) may progress to fulminant hepatic failure. In addition to determining the possible etiology, it is essential to determine the presence of hepatic dysfunction, as evidenced by encephalopathy (confusion, asterixis) and coagulopathy (prolonged INR). Common etiologies include:

  • Acute viral hepatitis
  • Drug-induced liver injury (DILI)
  • Toxin-induced liver injury
  • Ischemic hepatitis

Less commonly, the following can also be the cause of severe acute hepatocellular injury:

  • Autoimmune hepatitis
  • Acute Budd-Chiari syndrome
  • Acute bile duct obstruction


A detailed history may help determine the etiology. Ask about:

  • History of blood (possible acute viral hepatitis)
  • Medication history (possible drug-induced liver injury)
  • Diet/environmental history (possible toxin-induced liver injury)
  • Recent (within a day or so) symptoms (possible ischemic liver injury
  • Family or personal history of autoimmune disorders (possible autoimmune hepatitis)
  • Presence of abdominal distension (ascites) with or without peripheral edema and right upper quadrant pain (possible acute Budd-Chiari syndrome)
  • Compatible clinical picture with epigastric or right upper quadrant pain, a history of biliary surgery and/or gallstones (possible acute bile duct obstruction)

Physical examination

In general, there are no specific findings for acute hepatocellular injury. Jaundice may be present. Viral causes may be accompanied by common findings associated with viral syndrome (fever, rash, lymphadenopathy).

It is however essential to check for signs of hepatic encephalopathy (confusion, asterixis). Patients with confusion and/or asterixis should be urgently referred to a liver specialist or a transplant center.

Patients with asymptomatic jaundice should be urgently evaluated as well as those with significant weight loss.

Laboratory investigation

Initial investigation should be directed at evaluating the presence of hepatic dysfunction and investigating the etiology of the acute hepatitis.

Liver biopsy is generally not indicated in acute hepatocellular injury as it will show hepatic necrosis but will not be specific for its etiology.

To evaluate hepatic function:

  • Prothrombin time (PT) and INR
    Patients with abnormal prothrombin time or INR should be urgently referred to a liver specialist or a transplant center.
  • Rule out use of Warfarin (Coumadin). Should be considered a false elevation.

To investigate acute viral hepatitis:

  • Hepatitis A antibody of the IgM type (IgM anti-HAV)
  • Hepatitis B core antibody of the IgM type (IgM anti-HBc)
  • Hepatitis B surface antigen (HBsAg)
  • Hepatitis B core Total (IgM and IgG should be ordered if you suspect reactivation of chronic hepatitis B)
  • Hepatitis C viral load (the hepatitis C antibody may be negative)
  • Consider HBV-DNA titer*
  • Serologies and/or PCR for CMV, EBV and HSV (if the tests above are non-revealing)

*In the very early course of acute hepatitis B or C or in the immunocompromised patient, viral serologies may be negative. PCR testing should be obtained if suspicion for recent infection is high (for example, history of IV drug use or unsafe sexual contact within the last six months) or in the immunocompromised patient.

To investigate autoimmune hepatitis:

  • Antinuclear antibodies (ANA)
  • Anti-smooth muscle antibody (ASMA)
  • Serum protein electrophoresis (SPEP)

To investigate toxic damage:

  • Toxicology screen
  • Drug induced liver injury may require a liver biopsy for confirmation