What is the protocol for investigating elevated ferritin (iron storage protein) levels?

Protocol for Investigation of Elevated Ferritin

The diagnostic approach for hyperferritinemia requires first measuring fasting transferrin saturation (TS) and serum ferritin simultaneously, then searching for common causes including inflammation, liver disease, alcohol consumption, metabolic syndrome, and genetic disorders before proceeding to specialized testing. 1

Initial Evaluation

Step 1: Confirm Hyperferritinemia and Check Transferrin Saturation

• Measure fasting serum ferritin and transferrin saturation simultaneously
• Thresholds for concern: >300 μg/L in men, >200 μg/L in women 1

Step 2: Screen for Common Causes of Hyperferritinemia

• Inflammatory markers: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)
• Liver function tests: AST, ALT, GGT, alkaline phosphatase
• Complete blood count
• Metabolic panel: fasting glucose, lipid profile, HbA1c
• Alcohol consumption history
• Viral hepatitis serologies (HBV, HCV) 2, 1

Diagnostic Algorithm Based on Initial Results

If High Transferrin Saturation (>45% in women, >50% in men) + High Ferritin

• Suspect primary iron overload disorders
• Proceed with HFE genetic testing for C282Y and H63D mutations 2, 1
• Consider liver imaging (MRI) to quantify iron overload 3
• Consider liver biopsy if:
  • Serum ferritin >1000 μg/L
  • Elevated liver enzymes
  • Age >40 years
  • Hepatomegaly 2, 1

If Normal/Low Transferrin Saturation + High Ferritin

• Evaluate for secondary causes:
  • Inflammatory conditions (check CRP, ESR)
  • Liver disease (alcoholic, non-alcoholic fatty liver disease)
  • Malignancy (consider appropriate cancer screening)
  • Metabolic syndrome (check BMI, blood pressure, lipids, glucose)
  • Renal disease (check creatinine, eGFR)
  • Hemolytic disorders (check LDH, haptoglobin, reticulocyte count) 2, 1, 4

Special Considerations

For C282Y Homozygotes

• Diagnosis of HFE hemochromatosis requires evidence of increased iron stores, not just genetic testing 2
• If serum ferritin >1000 μg/L, consider liver biopsy to assess for fibrosis/cirrhosis 2

For C282Y/H63D Compound Heterozygotes or H63D Homozygotes

• Investigate other causes of hyperferritinemia first
• These genotypes rarely cause significant iron overload without cofactors 2, 1

For Patients with Chronic Kidney Disease

• Ferritin may not accurately reflect iron stores
• Consider additional tests: serum iron, transferrin saturation, soluble transferrin receptor 1

For Patients with Chronic Inflammatory Conditions

• Ferritin acts as an acute phase reactant
• Higher threshold (ferritin <100 μg/L) may still indicate iron deficiency in inflammatory states 1

Advanced Testing When Initial Evaluation is Inconclusive

• MRI for liver iron concentration (non-invasive gold standard) 3
• Consider genetic testing for non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) if:
  • Iron overload confirmed by MRI or liver biopsy
  • HFE testing is negative
  • Other hepatic and hematological disorders ruled out 2

Pitfalls and Caveats

• Extremely high ferritin levels (>10,000 μg/L) may suggest rare conditions like adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 4
• Malignancy is the most common cause of markedly elevated ferritin (>1000 μg/L) in clinical practice 4
• African Americans may have increased iron stores with high ferritin even with transferrin saturation in the upper reference range (not just above reference range) 5
• Avoid unnecessary genetic testing before ruling out common secondary causes of hyperferritinemia 2, 1
• Ferritin can remain elevated for months after resolution of the underlying cause

By following this systematic approach, clinicians can efficiently identify the cause of elevated ferritin and determine appropriate management strategies for patients with hyperferritinemia.