Can metformin cause increased liver function tests?

Metformin and Liver Function Tests

Metformin can improve liver function tests (LFTs) in patients with nonalcoholic fatty liver disease (NAFLD) but does not typically cause elevated LFTs. 1

Effects of Metformin on Liver Function

• Metformin has been shown to improve insulin resistance and transaminitis (elevated liver enzymes) in patients with NAFLD 1
• Studies demonstrate that metformin can reduce serum levels of liver function tests after several months of treatment 2
• Metformin does not appear to cause or exacerbate liver injury and is often beneficial in patients with nonalcoholic fatty liver disease 3

Mechanism of Action in Liver Disease

• Metformin increases peripheral glucose and fatty acid uptake while inhibiting lipogenesis and gluconeogenesis 1
• It activates AMPK (AMP-activated protein kinase), which can reduce fatty acid synthesis in the liver 4
• Metformin can reduce ROS (reactive oxygen species) production by inhibiting mitochondrial complex 1, which may reduce liver damage 4

Clinical Evidence

• In clinical trials, metformin has demonstrated improvement in liver function tests after 4 months of treatment 2
• While early pilot studies suggested metformin might improve liver histology, subsequent randomized controlled trials did not consistently support this finding 1
• The TONIC randomized controlled trial in children and adolescents with NAFLD showed that metformin led to a mean reduction in ALT of -41.7 U/L over 96 weeks, though this was not statistically superior to placebo 5

Safety Considerations

• Metformin is considered safe for use in patients with NAFLD and compensated cirrhosis with preserved renal function 1
• Current guidelines state: "Metformin can be used in adults with compensated cirrhosis and preserved renal function but should not be used in adults with decompensated cirrhosis, especially when there is concomitant renal impairment, because of the risk of lactic acidosis" 1
• Routine monitoring of transaminases before or during metformin treatment is not specifically required based on concerns about metformin hepatotoxicity 3

Important Caveats

• Metformin should be avoided in patients with decompensated cirrhosis due to increased risk of lactic acidosis 1
• The primary concern with metformin in liver disease is not hepatotoxicity but rather the risk of lactic acidosis in advanced liver disease 1
• Patients with cirrhosis, particularly those with encephalopathy, may have arterial hypoxemia, which heightens the risk of developing lactic acidosis with metformin 3
• Identifying patients with cirrhosis before initiating metformin is prudent, though cirrhosis can exist even with normal liver transaminases 3

Clinical Approach

• For patients with NAFLD without cirrhosis: Metformin can be safely used and may improve transaminase levels 1
• For patients with compensated cirrhosis (Child-Pugh A): Metformin can be used if renal function is preserved 1
• For patients with decompensated cirrhosis: Metformin should be avoided due to increased risk of lactic acidosis 1
• For patients with diabetes and NAFLD: Metformin is encouraged for management of diabetes in those with co-existing NAFLD 1

In summary, metformin typically does not cause elevated liver function tests but rather tends to improve them in patients with NAFLD. The primary concern with metformin use in liver disease is the risk of lactic acidosis in advanced liver disease, particularly decompensated cirrhosis with concomitant renal impairment.