Evaluation of Elevated Liver Enzymes

Initial Laboratory Workup

A complete blood count with platelets should be ordered to assess for cytopenias that may suggest advanced liver disease or other systemic conditions, as recommended by the European Association for the Study of the Liver 1
A hepatitis viral panel, including hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C antibody, should be ordered to determine the underlying cause of elevated liver enzymes, according to the American Association for the Study of Liver Diseases 1, 2
Autoimmune markers, such as anti-nuclear antibody, anti-smooth muscle antibody, and anti-mitochondrial antibody, should be ordered to assess for autoimmune hepatitis, as recommended by the European Association for the Study of the Liver 1, 3
Iron studies, including serum ferritin and transferrin saturation, should be ordered to assess for iron overload, according to the American Association for the Study of Liver Diseases 1, 5
Bilirubin levels, including total and direct, should be ordered to assess for cholestasis, as recommended by the European Association for the Study of the Liver 1
Gamma-glutamyl transferase should be ordered to confirm whether alkaline phosphatase elevation is of liver origin, according to the American Association for the Study of Liver Diseases 1, 6
Prothrombin time/INR should be ordered to assess synthetic liver function, as recommended by the European Association for the Study of the Liver 1

An abdominal ultrasound should be ordered to evaluate liver parenchyma, rule out biliary obstruction, and assess for signs of cirrhosis or fatty liver, according to the American Association for the Study of Liver Diseases 1, 5
Alpha-1-antitrypsin level should be ordered if there's suspicion of alpha-1-antitrypsin deficiency, as recommended by the European Association for the Study of the Liver 1
Ceruloplasmin should be ordered to rule out Wilson's disease, especially in younger patients, according to the American Association for the Study of Liver Diseases 1
Hepatitis A and E serology should be ordered if ALT is markedly elevated, as recommended by the European Association for the Study of the Liver 4
Cytomegalovirus and Epstein-Barr virus serology should be ordered in cases of marked transaminase elevation, according to the American Association for the Study of Liver Diseases 4
HBV DNA should be ordered if hepatitis B testing is positive, as recommended by the American Association for the Study of Liver Diseases 2
Lipid panel and hemoglobin A1c should be ordered to assess for metabolic syndrome components, according to the American Association for the Study of Liver Diseases 5

For patients on medications, all prescription and over-the-counter drugs should be reviewed, as drug-induced liver injury is a common cause of elevated liver enzymes, as recommended by the European Association for the Study of the Liver 1, 4
For patients with risk factors for non-alcoholic fatty liver disease, consider specialized imaging such as FibroScan or MRI, according to the American Association for the Study of Liver Diseases 5
For patients on immune checkpoint inhibitors with elevated liver enzymes, consider immune-related hepatitis and monitor closely, as recommended by the American Society of Clinical Oncology 3, 7
If initial workup is inconclusive and liver enzymes remain persistently elevated, consider liver biopsy for definitive diagnosis, according to the European Association for the Study of the Liver 1, 4

If liver enzymes are mildly elevated, recheck in 1-3 months, as recommended by the American Association for the Study of Liver Diseases 2
If liver enzymes are moderately elevated, consider more frequent monitoring, according to the American Association for the Study of Liver Diseases 2
If liver enzymes are severely elevated, urgent evaluation is warranted, as recommended by the American Association for the Study of Liver Diseases 2

Don't simply repeat the same liver enzyme panel without investigating the cause, as 84% of abnormal tests remain abnormal on retesting after 1 month, according to the European Association for the Study of the Liver 4, 6
Don't attribute elevated liver enzymes to a transient finding without proper evaluation, as 75% remain abnormal even after 2 years, as recommended by the European Association for the Study of the Liver 6
Don't forget to assess for extrahepatic causes of elevated liver enzymes, such as muscle injury or bone disease, according to the European Association for the Study of the Liver 1, 4
Don't overlook alcohol use as a potential cause of liver enzyme elevation, as recommended by the European Association for the Study of the Liver 1, 4