What is the initial workup for a patient with elevated ferritin (iron storage protein) levels?

Initial Workup for Elevated Ferritin Levels

The initial workup for elevated ferritin should begin with screening for common causes of hyperferritinemia including inflammation, liver disease, alcohol consumption, metabolic syndrome, and malignancy before proceeding to genetic testing for hemochromatosis. 1

Step 1: Assess for Common Causes of Hyperferritinemia

It's crucial to understand that approximately 90% of elevated serum ferritin cases are due to non-iron overload conditions 2. The initial evaluation should include:

• Inflammatory markers:

  • C-reactive protein (CRP)
  • Erythrocyte sedimentation rate (ESR)

• Liver function tests:

  • AST, ALT
  • Hepatitis serology
  • Autoimmune markers

• Metabolic assessment:

  • Fasting glucose
  • Lipid profile
  • Blood pressure
  • BMI calculation

• Additional tests:

  • Creatine kinase (CK) to check for muscle necrosis
  • Alcohol consumption history
  • Evaluation for malignancy if clinically indicated

Step 2: Iron Studies

Alongside ferritin, the following should be measured:

• Transferrin saturation (TS) - primary screening test for iron overload
  • TS > 45% suggests iron overload
  • Should be confirmed with a second determination (fasting sample advisable)
  • A normal ferritin with TS < 45% has 97% negative predictive value for excluding iron overload in individuals < 35 years 1

Step 3: Genetic Testing

If iron studies remain elevated after ruling out common causes:

• HFE genetic testing for C282Y and H63D mutations should be performed in patients with unexplained increased ferritin and increased transferrin saturation 3, 1
• Important: Diagnosis of hemochromatosis should not be based on C282Y homozygosity alone but requires evidence of increased iron stores 3

Ferritin Level Interpretation

Ferritin Level	Interpretation
>1000 μg/L	High risk of cirrhosis (20-45%) and warrants specialist referral [1,2]
>300 μg/L (males) or >200 μg/L (females) with elevated TS	Consider hemochromatosis workup [3]

Special Considerations

• Extremely high ferritin levels (>10,000 μg/L) may suggest rare conditions like adult-onset Still's disease, systemic juvenile idiopathic arthritis, or hemophagocytic lymphohistiocytosis/macrophage activation syndrome, though malignancy and infection remain more common causes 4

• Liver biopsy considerations: Should be offered to C282Y homozygous patients with serum ferritin above 1000 μg/L, elevated AST, hepatomegaly, or age over 40 years 3

When to Refer

Referral to a specialist (gastroenterologist, hematologist, or physician with interest in iron overload) is recommended when:

• Ferritin >1000 μg/L
• Cause remains unclear after initial evaluation
• Evidence of liver disease
• Confirmed genetic hemochromatosis 1, 2

Common Pitfalls to Avoid

1. Assuming all elevated ferritin indicates iron overload - Only about 10% of cases are related to true iron overload 5

2. Relying solely on ferritin levels - Ferritin is an acute phase reactant and can be elevated in many inflammatory conditions without iron overload 1

3. Missing iron deficiency with "normal" ferritin - In inflammatory states, ferritin levels up to 100 μg/L can still be consistent with iron deficiency 6

4. Failing to screen family members - Siblings of patients with HFE-related hemochromatosis have a 25% chance of being susceptible and should undergo screening 3