What is the significance of normal Liver Function Tests (LFTs) with elevated Alanine Transaminase (ALT) and Gamma-Glutamyl Transferase (GGT) levels?

From the Guidelines

If your liver function tests (LFTs) show elevated ALT (alanine aminotransferase) and GGT (gamma-glutamyl transferase) while other values are normal, this suggests liver inflammation or injury that requires medical evaluation, and you should consult with your healthcare provider promptly for proper diagnosis and management. The most recent and highest quality study, 1, published in 2023, highlights the importance of evaluating abnormal liver function tests, including elevated ALT and GGT, in the context of hepatocellular injury and potential underlying causes such as nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease, viral hepatitis, and autoimmune conditions.

Key Considerations

• Elevated ALT is directly linked to hepatocyte injury, and common causes include NAFLD, alcohol-induced liver disease, and viral hepatitis 1.
• GGT is sensitive to alcohol use and certain medications, and its elevation can help identify the underlying cause of liver injury 1.
• A detailed history, inventory of medications, and physical examination are essential in the initial evaluation of abnormal liver tests, including an assessment of risk factors for liver disease, medications, alcohol consumption, comorbid conditions, and signs and symptoms of hepatic disease 2.

Management and Further Evaluation

• Lifestyle modifications, such as reducing alcohol intake, maintaining a healthy weight, eating a balanced diet, and regular exercise, may be recommended by your doctor 1.
• Additional tests, like hepatitis screening, ultrasound imaging, or other specialized liver tests, may be ordered to determine the specific cause of elevated ALT and GGT 1.
• Medication adjustments might be necessary if drug-induced liver injury is suspected, and regular follow-up testing will be important to monitor liver health and the effectiveness of any interventions 1.

Clinical Context and Risk Factors

• The interpretation of abnormal liver chemistries must be taken in the clinical context of a given patient, considering risk factors for liver disease, medications, alcohol consumption, comorbid conditions, and signs and symptoms of hepatic disease 2.
• The evaluation of patients with ALT and GGT elevations should be directed toward establishing a diagnosis, rather than following an algorithm, and subsequent evaluation should be tailored to the specific clinical scenario of the individual patient 2.

From the FDA Drug Label

Abnormalities in liver enzymes have not been associated with Ursodiol therapy and, in fact, Ursodiol has been shown to decrease liver enzyme levels in liver disease. However, patients given Ursodiol should have SGOT (AST) and SGPT (ALT) measured at the initiation of therapy and thereafter as indicated by the particular clinical circumstances

The question about normal LFTs but raised ALT and GGT is not directly addressed by the provided drug labels 3 and 4. The labels discuss the lack of association between ursodiol therapy and liver damage, as well as the potential for ursodiol to decrease liver enzyme levels in liver disease. However, they do not provide specific guidance on the interpretation of raised ALT and GGT in the context of normal LFTs.

• Key points: + Ursodiol therapy has not been associated with liver damage. + Ursodiol may decrease liver enzyme levels in liver disease. + Patients on ursodiol should have liver enzymes monitored.
• Clinical decision: In the absence of direct evidence, it is not possible to draw a conclusion about the significance of raised ALT and GGT in the context of normal LFTs. Further evaluation and monitoring of liver enzymes may be necessary to determine the cause of the elevated ALT and GGT.

From the Research

Normal LFTs but Raised ALT and GGT

• The combination of normal liver function tests (LFTs) but raised alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels can be indicative of liver damage or disease, such as nonalcoholic steatohepatitis (NASH) 5, 6, 7.
• Elevated ALT levels have been associated with increased liver-related mortality, and a true healthy normal ALT level ranges from 29 to 33 IU/l for males and 19 to 25 IU/l for females 8.
• The degree of elevation of ALT and/or AST in the clinical setting helps guide the evaluation, and testing for viral hepatitis, nonalcoholic fatty liver disease, and alcoholic liver disease should be considered 8.
• Ursodeoxycholic acid (UDCA) in combination with vitamin E has been shown to improve liver function tests, including ALT and GGT levels, in patients with NASH 5, 7, 9.
• This combination therapy has also been found to decrease hepatocellular apoptosis and restore circulating levels of adiponectin, suggesting metabolic effects in addition to its beneficial cytoprotective properties 9.

Possible Causes and Treatments

• Nonalcoholic fatty liver disease (NAFLD) is one of the causes of a fatty liver, occurring when fat is deposited in the liver not due to excessive alcohol use, and is related to insulin resistance and the metabolic syndrome 6.
• The combination of alpha-lipoic acid and UDCA has been investigated as a therapeutic option for NAFLD, and has been found to reduce AST, ALT, and GGT values, and improve NAFLD fibrosis score and AST/ALT ratio 6.
• A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible 8.