What are the causes of elevated liver enzymes (transaminitis)?

From the Guidelines

Transaminitis should be managed by identifying and treating the underlying cause, with a focus on lifestyle modifications and avoiding potential triggers, as the liver has remarkable regenerative capacity and transaminitis often resolves with appropriate management of the underlying condition. The initial evaluation should include a complete medical history, physical examination, and liver function tests. If transaminitis is mild (less than 5 times the upper limit of normal) and the patient is asymptomatic, monitoring with repeat testing in 2-4 weeks may be appropriate while removing potential triggers like alcohol or hepatotoxic medications 1. For moderate to severe elevations, additional testing such as viral hepatitis serologies, ultrasound imaging, and autoimmune markers may be necessary.

Some key points to consider in the management of transaminitis include:

• Non-alcoholic fatty liver disease (NAFLD) is a common cause of transaminitis, and lifestyle modifications such as weight loss, avoiding alcohol, and managing diabetes or hyperlipidemia are often beneficial 1.
• Patients should avoid acetaminophen doses exceeding 2 grams daily and consult healthcare providers before taking new medications or supplements 1.
• The AST:ALT ratio can help differentiate between alcohol-induced fatty liver disease and metabolic disease-related fatty liver, with a ratio generally >2 in alcohol-induced fatty liver disease and <1 in metabolic disease-related fatty liver 1.
• Elevated alkaline phosphatase (ALP) levels may indicate cholestatic liver disease, and measurements of gamma-glutamyl transpeptidase (GGT) can help confirm whether an elevated ALP is of hepatic or nonhepatic origin 1.

Overall, the management of transaminitis should prioritize identifying and treating the underlying cause, with a focus on lifestyle modifications and avoiding potential triggers, as the liver has remarkable regenerative capacity and transaminitis often resolves with appropriate management of the underlying condition 1.

From the Research

Definition and Causes of Transaminitis

• Transaminitis refers to the elevation of liver transaminase levels, which can be caused by various factors, including nonalcoholic fatty liver disease, alcoholic liver disease, drug-induced liver injury, hepatitis B and C, and hereditary hemochromatosis 2.
• Other uncommon causes of transaminitis include alpha1-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease, while rare causes include extrahepatic sources such as thyroid disorders, celiac sprue, hemolysis, and muscle disorders 2.

Evaluation and Management of Transaminitis

• The initial evaluation of transaminitis should include an assessment for metabolic syndrome and insulin resistance, a complete blood count with platelets, measurement of serum albumin, iron, total iron-binding capacity, and ferritin, and hepatitis C antibody and hepatitis B surface antigen testing 2.
• The nonalcoholic fatty liver disease fibrosis score and the alcoholic liver disease/nonalcoholic fatty liver disease index can be helpful in the evaluation of mildly elevated transaminase levels 2.
• If testing for common causes is consistent with nonalcoholic fatty liver disease and is otherwise unremarkable, a trial of lifestyle modification is appropriate, while persistent elevation may require hepatic ultrasonography and further testing for uncommon causes 2.

Transaminitis in Inflammatory Bowel Disease

• Abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and primary sclerosing cholangitis is the most common hepatobiliary manifestation of IBD 3.
• Other hepatobiliary manifestations of IBD include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease 3.

Drug-Induced Transaminitis

• Certain drugs, such as oxaprozin, can cause transaminitis, and fulminant hepatic failure has been reported in rare cases 4.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) can also cause transaminitis, which is usually mild and reversible with discontinuation of the drug, but can be more likely to occur in the elderly or in patients receiving concurrent potentially hepatotoxic medications 4.

Transaminitis in Gene Therapy

• Elevated alanine transaminase (transaminitis) has been the most common adverse event observed during valoctocogene roxaparvovec gene therapy clinical trials, and corticosteroids can be used to mitigate transaminitis-associated decline in FVIII levels 5.

Transaminitis in Chronic Hepatitis B

• The goal of antiviral therapy in patients with chronic hepatitis B is to prevent cirrhosis and hepatocellular carcinoma, and the choice of treatment should take into consideration the clinical features of patients, antiviral efficacy, risk of developing resistance, and long-term safety profile 6.
• Ideal candidates for treatment are hepatitis B e antigen-positive patients with a prolonged phase of immune clearance and hepatitis B e antigen-negative patients with elevated levels of serum HBV DNA, abnormal alanine aminotransferase, and histologic evidence of moderate or severe liver necroinflammation and/or fibrosis 6.