What does high ferritin (iron storage protein) and low iron binding capacity indicate?

High Ferritin and Low Iron Binding Capacity: Diagnostic Implications

High ferritin levels combined with low iron binding capacity strongly indicates iron overload, most commonly seen in hemochromatosis, which requires prompt evaluation and management to prevent organ damage. 1

Pathophysiological Significance

High ferritin (iron storage protein) with low iron binding capacity represents a pattern consistent with iron overload conditions. This laboratory pattern indicates:

• Excessive iron accumulation in body tissues
• Saturation of transferrin (iron transport protein)
• Potential risk for organ damage due to iron deposition

Diagnostic Algorithm

1. Initial Assessment of Iron Parameters:

   • Elevated transferrin saturation (>45%)
   • High serum ferritin (>200 μg/L in men, >150 μg/L in women)
   • Low total iron binding capacity (TIBC)
   • Elevated liver transaminases may be present 1

2. Differential Diagnosis:

   A. Primary Iron Overload:

   • Hereditary Hemochromatosis (HH) - most common genetic cause
   • Most frequently due to HFE gene mutations (C282Y homozygosity)
   • Non-HFE hemochromatosis variants 1

   B. Secondary Iron Overload:

   • Transfusional iron overload
   • Ineffective erythropoiesis (thalassemia, myelodysplastic syndromes)
   • Chronic liver disease (alcoholic, viral, NAFLD)
   • Porphyria cutanea tarda 1

   C. Confounding Conditions (high ferritin without true iron overload):

   • Acute or chronic inflammation (ferritin as acute phase reactant)
   • Malignancy
   • Liver disease without iron overload
   • Alcohol excess 1

3. Confirmatory Testing:

   • Genetic testing for HFE mutations (C282Y, H63D) in suspected hemochromatosis
   • MRI for non-invasive quantification of iron in liver, heart, and other organs
   • Liver biopsy (if diagnosis remains unclear or to assess liver damage) 1

Clinical Implications

The clinical significance of high ferritin with low iron binding capacity depends on the underlying cause:

• In Hereditary Hemochromatosis: Progressive iron accumulation leads to:

  • Liver disease (fibrosis, cirrhosis, hepatocellular carcinoma)
  • Joint disease (arthropathy, chondrocalcinosis)
  • Cardiac complications (arrhythmias, cardiomyopathy)
  • Endocrine dysfunction (diabetes, hypogonadism)
  • Skin pigmentation 1

• In Secondary Iron Overload:

  • Organ damage similar to primary hemochromatosis
  • Increased mortality in transfusion-dependent patients
  • Cardiac complications as leading cause of death 1, 2

Management Considerations

For confirmed iron overload:

• Therapeutic phlebotomy: First-line treatment for hemochromatosis
• Iron chelation therapy: For secondary iron overload (transfusion-dependent)
• Monitoring: Regular assessment of ferritin levels, transferrin saturation, and organ function 1, 2

Important Caveats

1. Ferritin limitations: While elevated ferritin suggests iron overload, it's also an acute phase reactant that increases with inflammation, infection, and malignancy. Trends over time are more valuable than single measurements 1.

2. Diagnostic accuracy: The correlation between serum ferritin and actual body iron stores is not perfect, even in C282Y homozygotes 3.

3. Gender differences: Reference ranges for ferritin differ between men and women, with some evidence suggesting current ranges may underdiagnose iron deficiency in women 4.

4. Timing of testing: Morning samples are preferred for transferrin saturation, though fasting is not strictly necessary 1.

5. Screening considerations: For first-degree relatives of patients with hemochromatosis, screening should be considered due to the autosomal recessive inheritance pattern 1.

By recognizing this laboratory pattern early, clinicians can initiate appropriate diagnostic workup and prevent the serious complications associated with untreated iron overload disorders.