What are the causes of elevated Liver Function Tests (LFTs)?

From the Guidelines

Elevated liver function tests (LFTs) are most commonly caused by non-alcoholic fatty liver disease (NAFLD), alcohol-induced liver disease, viral hepatitis, and medication side effects, as supported by the most recent evidence 1.

Causes of Elevated LFTs

The causes of elevated LFTs can be broadly categorized into hepatocellular and cholestatic patterns.

• Hepatocellular injury is associated with elevated aminotransferases (ALT and AST) and can be caused by conditions such as fatty liver disease, viral hepatitis, autoimmune hepatitis, and medication-induced liver injury 1.
• Cholestatic patterns are characterized by elevated alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) and can be caused by conditions such as primary biliary cholangitis, primary sclerosing cholangitis, and bile duct obstruction 1.

Evaluation of Elevated LFTs

When evaluating elevated LFTs, it is essential to consider the pattern of elevation, the degree of elevation, and associated symptoms.

• A thorough history, including medication use, alcohol consumption, and family history, is crucial for diagnosis.
• Initial workup typically includes a comprehensive metabolic panel, complete blood count, coagulation studies, and specific tests for viral hepatitis, autoimmune markers, and iron studies depending on clinical suspicion.
• Imaging studies, such as ultrasound or CT scans, may be necessary to evaluate the liver and bile ducts.

Management of Elevated LFTs

The management of elevated LFTs depends on the underlying cause.

• For patients with suspected drug-induced liver injury, the study drug should be withheld, and a comprehensive medical evaluation should be triggered if patients have ALT ≥3× ULN and TBIL ≥2 × ULN 1.
• Liver biopsy may be useful in patients where liver biochemical tests fail to resolve or worsen despite removal of the study drug, and where other testing is unremarkable 1.
• A tiered approach towards investigating liver test abnormalities is recommended, evaluating the most likely alternative causes of liver injury first, before moving onto investigations for rarer causes of liver injury 1.

From the FDA Drug Label

Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1. 6% of patients in double-blind trials. In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses equivalent to 107 mg to 160 mg fenofibrate daily versus 1. 1% of patients treated with placebo. The following adverse reactions have been identified during post-approval use of fenofibrate ... hepatitis, cirrhosis, increased total bilirubin

The causes of elevated LFTs (Liver Function Tests) in patients taking fenofibrate include:

• Hepatotoxicity [see Warnings and Precautions (5.2)]
• Hepatitis
• Cirrhosis
• Increased total bilirubin Elevated LFTs were reported in 7.5% of patients taking fenofibrate versus 1.4% of patients taking placebo 2.

From the Research

Causes of Elevated LFTs

• Nonalcoholic fatty liver disease (NAFLD) is a common cause of elevated liver function tests (LFTs) 3, 4, 5, 6
• Alcoholic liver disease is also a common cause of elevated transaminase levels 5
• Other causes of elevated LFTs include:
  • Drug-induced liver injury 5
  • Hepatitis B and C 5
  • Hereditary hemochromatosis 5
  • Alpha1-antitrypsin deficiency 5
  • Autoimmune hepatitis 5
  • Wilson disease 5
  • Thyroid disorders 5
  • Celiac sprue 5
  • Hemolysis 5
  • Muscle disorders 5
• The pattern of elevated LFTs can help predict the degree of liver fibrosis and metabolic-associated comorbidities in patients with NAFLD 3
• Advanced fibrosis is more common in patients with a cholestatic pattern of elevated LFTs compared to those with a hepatocellular or mixed pattern 3
• Patients with NAFLD and elevated LFTs are at risk for progression to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma 4, 7, 6

Risk Factors for Elevated LFTs

• Obesity 4, 6
• Diabetes 3, 4, 6
• Metabolic syndrome 4, 5, 6
• Hyperinsulinemia 4
• Hypertriglyceridemia 3
• Hypertension 3
• Age 3

Evaluation and Management of Elevated LFTs

• Initial evaluation should include assessment for metabolic syndrome and insulin resistance, complete blood count, serum albumin, iron, total iron-binding capacity, and ferritin, and hepatitis C antibody and hepatitis B surface antigen testing 5
• Nonalcoholic fatty liver disease fibrosis score and alcoholic liver disease/nonalcoholic fatty liver disease index can be helpful in evaluation 5
• Lifestyle modification, including weight loss and dietary changes, is recommended for patients with NAFLD and elevated LFTs 4, 7, 6
• Pharmacological treatments are being developed for NAFLD, but currently, there is no approved therapy 7, 6