What is the appropriate workup for a patient with hyperferritinemia (elevated ferritin levels), not taking iron supplements, with normal serum iron levels and normal liver enzyme levels?

Workup for High Ferritin with Normal Iron and Liver Enzymes

The primary diagnostic approach for hyperferritinemia involves measuring fasting serum ferritin and transferrin saturation simultaneously, along with searching for common causes including inflammation, metabolic syndrome, malignancy, and genetic disorders. 1

Initial Evaluation

When encountering a patient with elevated ferritin levels, normal iron, and normal liver enzymes, the following workup should be performed:

1. Laboratory Tests:

   • Inflammatory markers: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 1
   • Complete blood count
   • Comprehensive metabolic panel
   • Transferrin saturation (TSAT) - crucial for differentiating causes 1
   • Viral hepatitis serologies (HBV, HCV) 1
   • Hemoglobin A1c and fasting glucose (to assess for diabetes/metabolic syndrome)

2. Clinical Assessment:

   • Alcohol consumption history 1
   • Body mass index (BMI) and assessment for metabolic syndrome
   • Family history of iron overload disorders

Interpretation of Results

• If transferrin saturation is >45% with hyperferritinemia: Consider hereditary hemochromatosis and proceed with genetic testing for HFE mutations (C282Y and H63D) 1, 2

• If transferrin saturation is normal or low with hyperferritinemia: Consider:

  • Inflammatory conditions (check elevated CRP/ESR)
  • Metabolic syndrome/NAFLD (particularly with BMI >30)
  • Malignancy (most common cause of markedly elevated ferritin >1000 μg/L) 3
  • Adult-onset Still's disease, hemophagocytic lymphohistiocytosis (with extremely high ferritin levels, often >10,000 μg/L) 3

Further Testing Based on Initial Results

• If inflammatory markers are elevated: Investigate for underlying inflammatory conditions or occult infection

• If metabolic syndrome features are present: Calculate ferritin/AST ratio - a ratio >20 is highly predictive of true iron overload (sensitivity 83.3%, specificity 78.6%) 4

• If ferritin >1000 μg/L: Consider liver biopsy to assess hepatic iron concentration and fibrosis, especially if patient is >40 years or has hepatomegaly 5, 1

• If no obvious cause is found: Consider MRI for non-invasive quantification of liver iron content 5

Special Considerations

• Hyperferritinemia is frequently found in patients with hepatic steatosis, but reflects true iron overload only when it persists despite dietary modifications 6

• In patients with features of iron overload but normal transferrin saturation, consider dysmetabolic hyperferritinemia syndrome (often associated with insulin resistance) 2, 6

• Even with normal liver enzymes, consider NASH as a potential cause, particularly in patients with metabolic abnormalities 6

Common Pitfalls to Avoid

• Don't assume normal iron levels exclude iron overload disorders: Serum iron can be normal in early hemochromatosis or fluctuate with diet

• Don't rely solely on ferritin levels: A ferritin level >50 μg/L doesn't automatically exclude iron deficiency in the presence of inflammation 7

• Don't miss malignancy: It's the most common cause of markedly elevated ferritin (>1000 μg/L) in tertiary care settings 3

• Don't automatically perform liver biopsy: With modern non-invasive methods like MRI, liver biopsy is rarely needed to assess iron overload 5

• Don't forget genetic testing: Consider HFE genetic testing in patients with suspected primary iron overload, even with normal transferrin saturation 1