What is the significance of elevated ferritin (iron storage protein) levels in patients with suspected liver disease?

Significance of Elevated Ferritin in Suspected Liver Disease

Elevated serum ferritin in patients with suspected liver disease is common and primarily indicates inflammation rather than true iron overload, though it should prompt evaluation for hemochromatosis when accompanied by elevated transferrin saturation.

Interpretation of Elevated Ferritin in Liver Disease

Common Causes in Liver Disease

• Mildly elevated serum ferritin is common in patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and is generally considered an epiphenomenon 1
• Ferritin can be elevated due to:
  • Systemic inflammation (most common cause in general population)
  • Hepatic inflammation/necroinflammatory liver disease
  • True iron overload (less common)
  • Combination of inflammation and iron overload

Clinical Significance

• Elevated ferritin correlates with more severe liver disease:
  • Associated with steatohepatitis diagnosis 2
  • Increases with worsening fibrosis stages up to pre-cirrhotic stage 3
  • Ferritin >1000 ng/mL is associated with high risk (20-45%) of cirrhosis 4
  • Ferritin >1.5× upper limit of normal is independently associated with advanced hepatic fibrosis and increased NAFLD Activity Score 2

Diagnostic Approach to Elevated Ferritin

Initial Evaluation

1. Confirm with repeat testing (preferably fasting sample) 1
2. Check transferrin saturation (TS) simultaneously 1
3. Evaluate for competing etiologies of liver disease and steatosis 1
4. Assess for inflammation (C-reactive protein, ESR) 4

When to Suspect Hemochromatosis

• Elevated serum ferritin AND elevated transferrin saturation (>45%) should lead to testing for genetic hemochromatosis 1
• Consider HFE gene mutation testing (C282Y, H63D) in this scenario 1

Liver Biopsy Considerations

• Consider liver biopsy to assess hepatic iron concentration and exclude significant hepatic injury in patients with:
  • Elevated ferritin AND homozygote/compound heterozygote C282Y mutation in HFE gene 1
  • Ferritin >1000 ng/mL (to assess for cirrhosis) 1, 4
  • Mixed pattern of iron deposition (associated with steatohepatitis) 3

Clinical Pearls and Pitfalls

Important Caveats

• Serum ferritin alone has low diagnostic accuracy for liver fibrosis in NAFLD patients 5
• Iron overload may be present with elevated ferritin and normal transferrin saturation in non-HFE iron overload 1
• Ferritin levels may decrease in cirrhosis despite significant iron overload 3
• Mutations in non-HFE iron genes (particularly ceruloplasmin) can be associated with hyperferritinemia and increased hepatic iron in NAFLD 6

Practical Recommendations

• In NAFLD patients, evaluate for metabolic risk factors (obesity, glucose intolerance, dyslipidemia) 1
• Patients with ferritin >1000 μg/L, suspected iron overload with elevated TSAT >45%, or elevated liver enzymes should be referred to gastroenterology or hematology 4
• Avoid iron supplementation when ferritin is significantly elevated (>100 μg/L) and transferrin saturation is not low 4

In conclusion, while elevated ferritin in liver disease often reflects inflammation rather than iron overload, it correlates with disease severity and should prompt appropriate evaluation for hemochromatosis when accompanied by elevated transferrin saturation.