What is the appropriate workup for elevated liver enzymes (transaminitis)?

From the Guidelines

The workup for transaminitis should begin with a thorough history and physical examination, followed by laboratory testing to determine the cause of elevated liver enzymes, as recommended by the most recent guidelines 1. The initial testing should include a complete metabolic panel, complete blood count, coagulation studies (PT/INR), and additional liver function tests including alkaline phosphatase, bilirubin, albumin, and gamma-glutamyl transferase.

• Viral hepatitis serologies (hepatitis A, B, C) should be ordered, along with tests for autoimmune causes such as antinuclear antibody, anti-smooth muscle antibody, and immunoglobulin levels.
• Metabolic and genetic causes should be evaluated with tests for hemochromatosis, Wilson's disease (ceruloplasmin), and alpha-1 antitrypsin deficiency.
• Abdominal ultrasound is the first-line imaging study to assess liver structure and rule out biliary obstruction, as suggested by the guidelines 1. For patients with risk factors, consider testing for alcoholic liver disease and non-alcoholic fatty liver disease.
• If the diagnosis remains unclear after initial testing, additional studies may include magnetic resonance imaging, endoscopic retrograde cholangiopancreatography, or liver biopsy. The severity of transaminitis guides management decisions, with mild elevations (less than 5 times normal) often allowing for outpatient monitoring, while severe elevations may require hospitalization, as indicated by the guidelines 1. Addressing the underlying cause is essential, whether that involves discontinuing hepatotoxic medications, treating viral infections, or managing metabolic conditions. The most recent and highest quality study 1 provides the best guidance for the workup and management of transaminitis, and should be prioritized in clinical decision-making.

From the Research

Transaminitis Workup

• The workup for transaminitis involves a stepwise evaluation based on the prevalence of diseases that cause mild elevations in transaminase levels 2
• 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

Common Causes of Transaminitis

• Nonalcoholic fatty liver disease is a common cause of mildly elevated liver transaminase levels, affecting up to 30% of the population 2
• Alcoholic liver disease, medication-associated liver injury, viral hepatitis (hepatitis B and C), and hemochromatosis are also common causes of transaminitis 2
• Less common causes include α(1)-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease 2
• Extrahepatic conditions such as thyroid disorders, celiac disease, hemolysis, and muscle disorders can also cause elevated liver transaminase levels 2

Autoimmune Hepatitis and Transaminitis

• The presence of anti-smooth muscle autoantibody (SMA) is well established in autoimmune hepatitis (AIH) 3
• Patients with positive SMA and raised ALT (>55IU/L) should be referred to secondary care for investigation, as the positive predictive value of SMA with raised ALT for AIH is 22% 3
• Antismooth muscle and antiactin antibodies are indirect markers of histological and biochemical activity of autoimmune hepatitis 4
• The persistence of high titers of ASMA and/or AAA in patients with AIH is associated with disease activity 4

Statin-Related Transaminitis

• Severe transaminitis associated with statin use is rare, occurring in 0.1% of patients 5
• Most cases of statin-related transaminitis are associated with drug interactions 5
• Transaminitis resolves upon statin discontinuation in most cases 5
• Less frequent liver enzyme monitoring may be suitable for most patients on statins, but continued monitoring is warranted for patients on concomitant medications or those with comorbid conditions 5