Can fatty liver disease cause hyperferritinemia (elevated iron levels)?

Can Fatty Liver Disease Cause Elevated Ferritin?

Yes, non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of elevated ferritin levels, accounting for over 90% of hyperferritinemia cases in outpatients when combined with other metabolic and inflammatory conditions. 1, 2 The elevation is primarily due to inflammation and metabolic dysfunction rather than true iron overload in most cases.

Understanding the Mechanism

In NAFLD, elevated ferritin typically reflects hepatocellular injury and insulin resistance rather than actual iron accumulation. 2 Approximately one-third of NAFLD patients demonstrate hyperferritinemia, usually with normal or only mildly elevated transferrin saturation. 3, 4 This pattern is critical because it distinguishes inflammatory hyperferritinemia from true iron overload disorders like hereditary hemochromatosis.

The pathophysiology involves:

• Ferritin acts as an acute phase reactant that rises during inflammation independent of actual iron stores 2, 3
• Metabolic dysfunction and insulin resistance trigger inflammatory pathways that increase ferritin production 4, 5
• In a smaller subset of NAFLD patients, a condition called dysmetabolic iron overload syndrome (DIOS) occurs, showing mild iron accumulation in reticuloendothelial cells 3, 5

Clinical Classification in NAFLD

The hyperferritinemia in NAFLD falls into three distinct patterns:

1. Pure inflammatory hyperferritinemia (majority of cases): Elevated ferritin without hepatic iron overload, driven entirely by inflammation 3

2. Dysmetabolic iron overload syndrome (DIOS): Hyperferritinemia with mild iron accumulation in reticuloendothelial cells, observed in approximately 15% of metabolic syndrome patients and half of those with NAFLD and hyperferritinemia 5, 6

3. Coexistent hereditary hemochromatosis (smallest group): NAFLD patients who also have HFE gene mutations causing true iron overload 3

Diagnostic Approach

The key to distinguishing NAFLD-related hyperferritinemia from true iron overload is measuring transferrin saturation alongside ferritin. 1, 7

Initial evaluation should include:

• Fasting transferrin saturation and serum ferritin measured simultaneously 1, 8
• Liver enzymes (ALT, AST) to assess hepatocellular injury 1, 2
• Inflammatory markers (CRP, ESR) 1, 2
• Metabolic parameters (BMI, blood pressure, glucose, lipids) 1

Interpretation algorithm:

• If transferrin saturation <45% with elevated ferritin: NAFLD-related inflammation is the likely cause, not iron overload 1, 2, 7
• If transferrin saturation ≥45% with elevated ferritin: Proceed with HFE genetic testing for C282Y and H63D mutations to evaluate for hereditary hemochromatosis 1, 7
• Mildly elevated ferritin (200-300 μg/L in males, >200 μg/L in females) is common in NAFLD and does not necessarily indicate increased iron stores 1

Critical Pitfall to Avoid

Never use ferritin alone without transferrin saturation to diagnose iron overload. 2, 7 This is the most common diagnostic error. In NAFLD, ferritin elevation reflects metabolic dysfunction and inflammation, while transferrin saturation remains normal or only minimally elevated. Conversely, in hereditary hemochromatosis, both ferritin and transferrin saturation are typically elevated together. 1

Management Implications

Treatment should target the underlying NAFLD rather than the elevated ferritin itself when transferrin saturation is normal. 7 This includes:

• Weight loss and lifestyle modifications 1, 3
• Management of metabolic syndrome components 1
• Phlebotomy is only indicated when there is documented hepatocellular iron overload (not just elevated ferritin), and should not be used when hyperferritinemia is purely inflammatory 3

In the subset of NAFLD patients with confirmed iron accumulation (DIOS), iron depletion by phlebotomy may improve liver histology and enzymes. 9 However, a randomized trial showed that phlebotomy in NAFLD patients with hyperferritinemia improved histological liver damage in 67% versus 22% in controls, but this benefit requires confirmation of actual iron overload, not just elevated ferritin. 9

When to Consider Liver Biopsy

Liver biopsy should be considered in NAFLD patients with ferritin >1000 μg/L, elevated liver enzymes, or age >40 years to assess for advanced fibrosis. 1 However, in patients with ferritin <1000 μg/L, normal transaminases, and no hepatomegaly, the risk of advanced liver fibrosis is very low (negative predictive value 94%). 8