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

Workup for Elevated Ferritin

The appropriate workup for elevated ferritin should begin with serum transferrin saturation (TS) measurement, followed by HFE genetic testing for C282Y and H63D mutations if iron studies are elevated, as this approach allows for proper differentiation between true iron overload conditions and other causes of hyperferritinemia. 1

Initial Evaluation

1. First-line laboratory tests:

   • Transferrin saturation (TS) - primary screening test (TS >45% suggests iron overload)
   • Confirm elevated TS with a second determination (fasting sample advisable)
   • Complete iron studies
   • Liver function tests
   • Inflammatory markers (CRP, ESR)
   • Complete blood count

2. Clinical assessment for common causes of elevated ferritin:

   • Alcohol consumption history
   • Metabolic syndrome features
   • Obesity
   • Diabetes
   • Signs of liver disease
   • History of blood transfusions
   • Family history of iron overload disorders

Interpretation of Ferritin Levels

• <10 μg/L: Severe iron deficiency
• <30 μg/L: Iron deficiency without inflammation
• 30-100 μg/L: Possible iron deficiency or anemia of chronic disease
• 50-100 μg/L: Target maintenance range for most patients
• >100 μg/L: Possible anemia of chronic disease or iron overload
• >1000 μg/L: High risk of cirrhosis (20-45%) 1

Differential Diagnosis

It's crucial to recognize that 90% of elevated serum ferritin cases are due to non-iron overload conditions 2. Common causes include:

1. Inflammatory conditions:

   • Infections
   • Autoimmune disorders
   • Adult-onset Still's disease
   • Hemophagocytic lymphohistiocytosis

2. Liver diseases:

   • Hepatitis
   • Non-alcoholic fatty liver disease (NAFLD)
   • Alcoholic liver disease

3. Malignancies:

   • Various cancers (most frequent cause of markedly elevated ferritin in one study) 3

4. Iron overload syndromes:

   • Hereditary hemochromatosis
   • Transfusion-dependent disorders
   • Dyserythropoietic anemias

5. Other conditions:

   • Metabolic syndrome
   • Chronic kidney disease
   • Anemia of chronic disease

Further Testing Based on Initial Results

1. If TS >45% and elevated ferritin:

   • HFE genetic testing for C282Y and H63D mutations 1
   • Consider liver MRI for iron quantification (T2 or T2* relaxometry) 4

2. If normal TS with elevated ferritin:

   • Evaluate for inflammatory conditions (CRP, ESR)
   • Assess liver function (comprehensive liver panel)
   • Screen for metabolic syndrome
   • Consider hereditary hyperferritinemia syndromes 5

3. If ferritin >1000 μg/L:

   • Refer to a gastroenterologist, hematologist, or physician with interest in iron overload 1, 2
   • Consider liver biopsy in selected cases
   • Evaluate for malignancy if clinically indicated

Common Pitfalls to Avoid

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

• Missing rare genetic causes: Hereditary hyperferritinemia can present with normal transferrin saturation 5

• Premature diagnosis of hemochromatosis: Always confirm with genetic testing and/or liver iron assessment before initiating treatment 1

• Inappropriate venesection therapy: Venesection is not appropriate for 90% of elevated ferritin cases that are due to non-iron overload conditions 2

• Overlooking malignancy: In one study, malignancy was the most frequent cause of markedly elevated ferritin (>1000 μg/L) 3

When to Refer

• Ferritin >1000 μg/L
• Elevated liver enzymes with hyperferritinemia
• Suspected iron overload with elevated TSAT >45%
• Unclear cause after initial evaluation
• Confirmed hereditary hemochromatosis requiring management 1, 2