Liver Enzymes in Hepatic Iron Overload
Liver enzymes (ALT, AST) are frequently elevated in hepatic iron overload, and this elevation serves as a key clinical indicator for assessing the severity of iron-related liver damage and determining the need for liver biopsy.
Pattern of Enzyme Elevation
Transaminase elevations occur commonly in iron overload states and should prompt further investigation for the degree of hepatic fibrosis. According to the EASL 2022 guidelines, liver biopsy can be performed to assess liver fibrosis if liver enzymes are increased, particularly when serum ferritin is higher than 1,000 μg/L 1. The American Association for the Study of Liver Diseases similarly recommends liver biopsy to stage the degree of liver disease in C282Y homozygotes or compound heterozygotes if liver enzymes (ALT, AST) are elevated or if ferritin is >1000 μg/L 1.
Clinical Significance of Enzyme Monitoring
The presence of abnormal transaminases in the setting of iron overload indicates potential hepatocellular injury and warrants aggressive evaluation, even when ferritin levels are below traditional thresholds. The EASL guidelines note that if serum ferritin is lower than 1,000 μg/L but transaminases are increased, a liver biopsy may still be considered 1. This is particularly important because a serum ferritin <1,000 μg/L, in the absence of hepatomegaly, thrombocytopenia, and abnormal transaminases was associated with a negative predictive value of 94% for advanced liver fibrosis 1.
Mechanisms of Enzyme Elevation
The elevation of liver enzymes in iron overload reflects hepatocellular damage through several pathways:
- Oxidative stress from excess free iron causes direct hepatocellular death by triggering organelle dysfunction 2
- Iron-induced activation of inflammatory cells including Kupffer cells and hepatic stellate cells promotes ongoing liver injury 2
- Impaired iron export mechanisms perpetuate hepatic iron retention, with down-regulation of ferroportin-1 and hemojuvelin contributing to continued cellular damage 3
Monitoring Recommendations
Liver enzymes should be monitored at least annually in all patients with iron overload. In patients receiving prophylactic hemin therapy (which can cause secondary iron overload), liver enzymes should be monitored at least annually, with more frequent monitoring (every 3-6 months) for ferritin and iron levels 1.
Common Pitfalls
A critical caveat is that elevated liver enzymes in the presence of iron overload should prompt investigation for alternative etiologies, not just attribution to iron alone. The cause of liver enzyme elevation in iron overload is not always well defined, and abnormal liver enzymes should prompt diagnostic investigation for concomitant conditions such as nonalcoholic steatohepatitis, viral hepatitis, or alcohol-related liver disease 1. In some cases, liver biopsy may help diagnose these concomitant conditions 1.
Treatment Response
Phlebotomy treatment in iron-overloaded patients improves liver function tests, demonstrating the reversibility of iron-induced hepatocellular injury. Research shows that phlebotomy treatment reduces serum ferritin, transferrin saturation, and improves liver function tests in patients with nonalcoholic fatty liver disease and iron overload 3. This improvement in liver enzymes with iron depletion provides evidence that the enzyme elevation is directly related to iron toxicity 4.