What is the workup for elevated Liver Function Tests (LFTs) three times the upper limit of normal (ULN)?

From the Guidelines

For elevated LFTs 3x ULN, a comprehensive workup should include monitoring patient for abnormal liver blood tests, reviewing medications and supplements that may cause hepatotoxicity, and considering liver biopsy if steroid-refractory or if concern for other differential diagnoses 1. When evaluating elevated LFTs, it is crucial to consider the potential causes and take a systematic approach to diagnosis.

• Initial steps should include monitoring liver blood tests such as AST, ALT, and bilirubin before each infusion and/or considering weekly monitoring if grade 1 LFT elevations are present 1.
• Reviewing medications and supplements that may cause hepatotoxicity is also essential, as well as ruling out abnormal liver enzymes from development or progression of liver metastases 1.
• For grade 2 or higher LFT elevations, workup for other causes of elevated liver enzymes should be considered, including viral hepatitis, alcohol history, iron studies, thromboembolic event, or potential liver metastasis from primary malignancy 1.
• Additional testing such as blood work and imaging (ultrasound and cross-sectional imaging) may be necessary to determine the underlying cause of elevated LFTs 1.
• If suspicion for primary autoimmune hepatitis is high, consideration of ANA/ASMA/ANCA testing may be warranted, and for isolated elevation of transaminases, checking CK for other etiologies should be considered 1.

From the Research

Elevated LFTs 3x ULN Workup

• The workup for elevated liver function tests (LFTs) 3x upper limit of normal (ULN) involves a stepwise evaluation based on the prevalence of diseases that cause mild elevations in transaminase levels 2
• The most common cause of mildly elevated LFTs is nonalcoholic fatty liver disease, which can affect up to 30 percent of the population 2
• Other common causes include alcoholic liver disease, medication-associated liver injury, viral hepatitis (hepatitis B and C), and hemochromatosis 2
• Less common causes include α(1)-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease 2
• Extrahepatic conditions (e.g., thyroid disorders, celiac disease, hemolysis, muscle disorders) can also cause elevated LFTs 2

Autoantibody Testing

• Autoantibody testing is key to the diagnosis and management of autoimmune liver diseases 3
• The presence of anti-smooth muscle autoantibody (SMA) in autoimmune hepatitis (AIH) is well established, and patients with positive SMA and raised ALT (>55IU/L) should be referred to secondary care for investigation 4
• The diagnostic autoantibodies associated with AIH-1 are anti-nuclear (ANA) and/or anti-smooth muscle (SMA) autoantibodies, whereas anti-liver kidney microsomal type 1 (anti-LKM1) and/or anti-liver cytosol type 1 (anti-LC1) define AIH type 2 (AIH-2) 5

Initial Testing

• Initial testing should include a fasting lipid profile; measurement of glucose, serum iron, and ferritin; total iron-binding capacity; and hepatitis B surface antigen and hepatitis C virus antibody testing 2
• If test results are normal, a trial of lifestyle modification with observation or further testing for less common causes is appropriate 2
• Additional testing may include ultrasonography; measurement of α(1)-antitrypsin and ceruloplasmin; serum protein electrophoresis; and antinuclear antibody, smooth muscle antibody, and liver/kidney microsomal antibody type 1 testing 2

Referral for Further Evaluation

• Referral for further evaluation and possible liver biopsy is recommended if transaminase levels remain elevated for six months or more 2