What is the next step in managing a patient with elevated ferritin (Ferritin) levels, normal iron (Iron), normal Total Iron-Binding Capacity (TIBC), and normal Hemoglobin (HGB) and Hematocrit (HCT) levels?

Management of Elevated Ferritin with Normal Iron, TIBC, and Hemoglobin/Hematocrit

The next step in managing a patient with elevated ferritin, normal iron, normal TIBC, and normal hemoglobin/hematocrit levels is to evaluate for non-iron overload causes, particularly fatty liver disease, inflammation, and metabolic syndrome, before considering genetic testing for hemochromatosis if transferrin saturation is >45-50%. 1

Initial Diagnostic Approach

1. Calculate transferrin saturation:

   • Divide serum iron by TIBC to determine transferrin saturation percentage
   • This is crucial for differentiating between true iron overload and inflammatory hyperferritinemia 1

2. Evaluate for common non-iron overload causes:

   • Inflammatory conditions (measure C-reactive protein)
   • Fatty liver disease (most common cause of elevated ferritin with normal transferrin saturation)
   • Alcoholic liver disease
   • Metabolic syndrome
   • Liver damage (check liver enzymes - ALT, AST)
   • Recent iron infusion (can falsely elevate ferritin for up to 4 weeks) 2, 1

Decision Algorithm Based on Transferrin Saturation

If transferrin saturation is normal (<45%):

• Focus on management of non-alcoholic fatty liver disease (NAFLD)
• Recommend lifestyle modifications:
  • Weight loss
  • Regular physical activity
  • Blood pressure control
  • Limiting alcohol intake
• Monitor liver function tests regularly 1

If transferrin saturation is elevated (>45% in females, >50% in males):

• Order HFE gene testing for p.C282Y mutations to diagnose hereditary hemochromatosis
• Consider liver biopsy or MRI to assess:
  • Hepatic iron concentration
  • Pattern of iron deposition
  • Degree of fibrosis and inflammation 1

Additional Diagnostic Tests to Consider

• Liver biochemistry panel: To assess liver function and potential liver disease
• Inflammatory markers: C-reactive protein to assess contribution of inflammation
• Hematologic evaluation: To rule out chronic hematologic diseases that can cause iron overload
• MRI of the liver: To detect and quantify hepatic iron excess with high sensitivity and specificity 1, 3

Common Pitfalls and Caveats

1. Multiple causes: More than 40% of patients with hyperferritinemia have several causes simultaneously present 3

2. Discordant iron parameters: Ferritin may be elevated due to its acute phase reactivity while transferrin saturation remains normal, especially in inflammatory conditions 2

3. Timing of testing: Iron parameters should not be evaluated within 4 weeks of IV iron administration as circulating iron interferes with the assay 2

4. Rare causes: Consider less common causes if initial evaluation is negative:

   • Adult-onset Still's disease
   • Hemophagocytic lymphohistiocytosis
   • Malignancy (most frequent condition in patients with markedly elevated ferritin >1000 μg/L) 4

5. Misdiagnosis risk: Limiting clinical evaluation to only those individuals with both increased ferritin and increased transferrin saturation may miss individuals with increased iron stores 5

Remember that early identification and treatment of iron overload before development of cirrhosis and/or diabetes significantly reduces morbidity and mortality 1. However, in the context of normal iron, TIBC, and hemoglobin/hematocrit, inflammatory or metabolic causes of hyperferritinemia are most likely.