Elevated transaminases

Elevated transaminases are typically a sign of hepatocellular injury and most commonly caused by alcohol-associated liver disease or metabolic dysfunction associated steatotic liver disease (MASLD). The initial diagnostic workup comprises liver chemistries that include both alanine transaminase (ALT) and aspartate transaminase (AST), and an abdominal ultrasound. If signs of acute liver failure are present (e.g., altered mental status, jaundice), initiate urgent management and consult hepatology. A referral for liver biopsy may be considered for patients in whom the etiology remains unclear.

• Elevated transaminases: elevation of ALT and/or AST above the upper limit of normal (ULN) ^[1]
  • Massively elevated transaminases: ALT and/or AST > 10,000 U/L
  • Severely elevated transaminases: ALT and/or AST > 15× ULN
  • Moderately elevated transaminases: ALT and/or AST 5–15× ULN
  • Mildly elevated transaminases: ALT and/or AST 2–5× ULN
  • Borderline elevated transaminases: ALT and/or AST < 2× ULN
• Hepatocellular injury pattern: disproportionate elevation of AST and ALT compared to alkaline phosphatase (ALP) ^[1]
• Mixed injury pattern: proportionally elevated ALP and transaminases ^[1]
• Cholestatic injury pattern: disproportionate elevation of ALP compared to AST and ALT (see “Jaundice and cholestasis”) ^[1]

The causes of cholestatic liver injury are covered in “Jaundice and cholestasis.”

The ratio of AST serum levels to ALT serum levels can be used to narrow down the etiology of hepatocellular injury.

Focused history ^[1]

• Family history: AIH, hemochromatosis, Wilson disease, AATD
• Current symptoms
  • May be absent
  • Nonspecific, e.g., fatigue, nausea, unintentional weight loss
• Exposures
  • Alcohol
  • Hepatotoxic medications, e.g., acetaminophen, isoniazid, phenytoin
  • Foraged mushrooms, e.g., Amanita phalloides
  • Herbal supplements, e.g., Ephedra sinica ^[4]
  • Viral hepatitis
• Cardiometabolic risk factors for MASLD

Patients with nonsevere elevation of transaminases are often asymptomatic and have normal physical examination findings.

Focused examination ^[1]

Assess for any of the following:

• Signs of acute liver failure
• Signs of chronic liver disease
• Features of metabolic syndrome, e.g., abdominal obesity, hypertension
• Signs of specific conditions, e.g., Kayser-Fleischer rings

The following focuses on diagnostics for patients with a hepatocellular injury pattern. See “Diagnostics for cholestasis” and “Cholestatic causes of conjugated hyperbilirubinemia” in patients with a cholestatic or mixed injury pattern.

Approach ^[1]

• Perform a focused clinical evaluation.
• Consider causes based on patient history, e.g., alcohol-associated fatty liver, MASLD, or drug-induced liver injury.
• Order routine laboratory studies for all patients, including repeat transaminases to confirm true elevation.
• Obtain imaging and additional laboratory studies depending on severity.
  • Borderline or mild elevation: Consider 3–6 months of observation before repeat testing of AST, ALT, and ALP; obtain additional testing if elevation persists or worsens. ^[1]
  • All other patients: Obtain simultaneously with routine laboratory studies.
• Consider referral for liver biopsy if the etiology remains unknown.

In patients with elevated transaminases, advise discontinuation of any hepatotoxic medications and avoidance of alcohol.

Routine laboratory studies ^[1]

• Liver chemistries
  • Transaminases ^[1]
    • ALT > 33 IU/L (♂) or > 25 IU/L (♀)
    • AST > 18 IU/L
  • ALP and total bilirubin: to establish injury pattern
  • Albumin: to assess hepatic synthetic function
• CBC: to assess for thrombocytopenia
• Coagulation studies: to assess hepatic synthetic function

For patients with transaminases < 5× ULN (i.e., borderline or mild), consider 3–6 months of observation if initial routine studies do not reveal a diagnosis. ^[1]

Additional studies ^[1]

Severe elevation of transaminases

• Laboratory studies
  • Hepatitis C serology, hepatitis B serology, anti-HAV IgM, hepatitis E serology if positive travel history to endemic areas
  • PCR for nonhepatotropic viruses: HSV, EBV, CMV
  • Ceruloplasmin to screen for Wilson disease in patients < 55 years of age
  • Autoimmune hepatitis serology, e.g., ANA, ASMA, SPEP, Anti LKM1
  • Serum and urine toxicology testing to assess for drug-induced liver injury
• Doppler abdominal ultrasound

For patients with severely elevated transaminases, order initial and additional laboratory studies concomitantly, along with an abdominal ultrasound.

Nonsevere elevation of transaminases

• All patients
  • Laboratory studies
    • Iron studies to screen for iron overload disorders
    • Hepatitis C serology, hepatitis B serology
    • Ceruloplasmin to screen for Wilson disease in patients < 55 years of age
    • Autoimmune hepatitis serology, e.g., ANA, ASMA, SPEP
    • α1-antitrypsin (AAT) levels for AATD
  • Abdominal ultrasound
• Moderately elevated transaminases: Also test for hepatitis A (anti-HAV IgM, anti-HAV IgG) in patients with acute hepatitis and possible exposure.
• Borderline or mildly elevated transaminases: Consider further testing based on clinical suspicion, e.g., for tick-borne diseases, celiac disease, hypothyroidism, and/or metabolic syndrome. ^[5]

• Discontinue alcohol and hepatotoxic medications.
• Provide management of acute liver failure as indicated, e.g.:
  • Emergency stabilization
  • Consult with hepatology urgently.
  • Request transfer of care to a liver transplant center.
• Base additional management on the underlying cause.