What does high ferritin (iron) level mean?

High Ferritin: Causes and Diagnostic Approach

Elevated ferritin levels primarily indicate inflammation, metabolic syndrome, liver disease, or true iron overload, and require systematic evaluation to determine the underlying cause. 1

Common Causes of Hyperferritinemia

• The most common causes of elevated ferritin (>90% of cases) include chronic alcohol consumption, inflammation, cell necrosis, tumors, and non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome 1
• Ferritin is an acute phase reactant that increases during inflammatory and malignant conditions, often without representing true iron overload 2
• Hereditary hemochromatosis (HH), particularly related to HFE gene mutations (C282Y homozygosity), is an important but less common cause of elevated ferritin 3, 1
• Non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) can also cause hyperferritinemia 1
• Secondary causes include alcoholic liver disease, viral hepatitis, NAFLD, acute hepatitis, systemic inflammatory response syndrome, adult-onset Still's disease, solid tumors, lymphomas, and infections 1, 2

Diagnostic Approach

Step 1: Initial Assessment

• Measure transferrin saturation (TS) along with serum ferritin 1, 4
• Normal TSAT is typically not more than 45-50% saturated with iron 4
• A normal ferritin range in adults is generally between 100-300 ng/mL 4

Step 2: Interpretation Based on Results

• If TSAT < 45% with elevated ferritin: Suggests non-iron overload causes (inflammation, liver disease, malignancy) 3, 1
• If TSAT ≥ 45% with elevated ferritin: Suggests potential iron overload requiring further evaluation 3, 1

Step 3: Further Evaluation

• For suspected iron overload (TSAT ≥ 45% and elevated ferritin):
  • Perform HFE genetic testing for C282Y and H63D mutations 3
  • Consider liver biopsy or MRI for hepatic iron concentration assessment if needed 3
• For non-iron overload causes:
  • Check inflammatory markers (CRP, ESR) 2
  • Evaluate liver function tests 2
  • Consider screening for metabolic syndrome 1

Clinical Significance and Management

When to Suspect True Iron Overload

• TSAT persistently above 45% 3, 4
• Ferritin consistently elevated above 500-1000 ng/mL 4
• Presence of end-organ damage (liver, heart, pancreas) 4
• Confirmed hemochromatosis genetics (C282Y homozygosity) 3

Important Clinical Pearls

• In confirmed hemochromatosis, serum ferritin >1,000 ng/mL is an accurate predictor of hepatic fibrosis/cirrhosis 3
• Serum ferritin has high sensitivity but low specificity for iron overload 1
• In the general population, iron overload is not the most common cause of elevated ferritin 1
• Anemia of chronic disease typically presents with serum ferritin >100 μg/L and TSAT <16% 2

Treatment Considerations

• For confirmed iron overload:
  • Therapeutic phlebotomy is the standard treatment 3
  • Target serum ferritin to less than 50 μg/L initially, then maintain at 50-100 μg/L 3
  • Iron chelation therapy (e.g., deferasirox) may be considered for patients who cannot undergo phlebotomy 5
• For non-iron overload causes:
  • Treatment should target the underlying condition 2
  • Dietary interventions alone are insufficient for treating established iron overload 3

Common Pitfalls to Avoid

• Assuming all elevated ferritin represents iron overload 1, 2
• Initiating phlebotomy without confirming iron overload 3
• Overlooking inflammation as a common cause of elevated ferritin 1, 2
• Failing to monitor for end-organ damage in confirmed iron overload 3
• Continuing iron chelation therapy when serum ferritin falls below 500 mcg/L 5