What are the diagnostic and treatment approaches for abnormal iron stores, including iron deficiency and overload?

Diagnostic and Treatment Approaches for Iron Stores Abnormalities

The diagnosis of iron status abnormalities should begin with transferrin saturation (TS) and serum ferritin measurements as the initial laboratory tests, with follow-up testing based on these results to determine appropriate treatment for either iron deficiency or iron overload. 1

Diagnostic Approach for Iron Status Evaluation

Initial Laboratory Testing

• Transferrin saturation (TS) and serum ferritin should be obtained simultaneously as the primary screening tests for both iron deficiency and iron overload 2, 1
• Fasting transferrin saturation is the most sensitive initial test for hemochromatosis, with values ≥45% having high sensitivity for detecting genetic hemochromatosis 2, 1
• Normal ranges for serum ferritin vary by sex: typically 15-200 μg/L for women and 30-300 μg/L for men 1

Interpretation of Initial Test Results

• Iron deficiency: Low serum ferritin (<30 μg/L) with low transferrin saturation (<20%) 2
• Iron overload: Elevated transferrin saturation (>50% for women, >60% for men) and elevated serum ferritin (>200 μg/L for women, >300 μg/L for men) 2
• Functional iron deficiency: High serum ferritin with low transferrin saturation, commonly seen in chronic inflammatory conditions 3, 4

Follow-up Testing Based on Initial Results

• For suspected iron overload with elevated TS and ferritin, genetic testing for HFE mutations (C282Y and H63D) should be performed 2, 1
• For iron deficiency with normal or low ferritin but persistent symptoms, additional testing may include reticulocyte hemoglobin content or percentage of hypochromic red cells 4
• When standard iron markers are inconclusive, tissue biopsy (particularly liver) or MRI quantification of iron content may be necessary 2

Treatment of Iron Deficiency

Oral Iron Therapy

• Oral iron supplementation is effective for mild iron deficiency in clinically stable patients 2
• Ferrous sulfate (65mg elemental iron per 324mg tablet) is commonly used, providing 362% of the recommended daily intake 5
• No more than 100mg elemental iron per day is recommended to minimize gastrointestinal side effects 2
• Treatment should continue until hemoglobin normalizes and ferritin levels indicate replenished iron stores (>100 μg/L) 2

Intravenous Iron Therapy

• Intravenous iron is indicated for patients with:
  • Moderate to severe anemia (Hb <10 g/dL) 2
  • Intolerance to oral iron preparations 2
  • Active inflammatory bowel disease or other conditions where oral iron may exacerbate symptoms 2
• After successful IV iron treatment, re-treatment should be initiated when serum ferritin drops below 100 μg/L or hemoglobin falls below gender-specific thresholds (12 g/dL for women, 13 g/dL for men) 2

Management of Iron Overload

Diagnostic Confirmation

• HFE genetic testing for C282Y and H63D mutations is recommended when iron overload is suspected based on elevated transferrin saturation and ferritin 2, 1
• C282Y homozygosity confirms hereditary hemochromatosis, while compound heterozygosity (C282Y/H63D) or other patterns require further investigation 1
• Liver biopsy should be considered in C282Y homozygotes with serum ferritin >1,000 μg/L, elevated liver enzymes, or age >40 years to assess for cirrhosis 1

Treatment Options

• Phlebotomy is the mainstay of treatment for hereditary hemochromatosis and other primary iron overload conditions 2, 6
• For secondary iron overload (e.g., transfusion-dependent conditions), iron chelation therapy is recommended when:
  • Serum ferritin reaches 1,000 ng/mL 2
  • Transfusion need is ≥2 units/month for more than one year 2
  • There is evidence of organ dysfunction related to iron overload 2
• Iron chelation therapy should be monitored according to specific guidelines for the chelation product being used 2

Monitoring During Treatment

• For patients on phlebotomy, monitor ferritin levels and hemoglobin to guide frequency of procedures 2
• For patients on chelation therapy, monitor serum ferritin every 3 months 2
• Cardiac MRI with T2* measurement is recommended for monitoring cardiac iron deposition in transfusion-dependent patients 2

Special Considerations

Secondary Causes of Iron Abnormalities

• Investigate for underlying conditions when iron studies are abnormal:
  • For iron deficiency: gastrointestinal bleeding, malabsorption, or increased requirements 2
  • For iron overload without HFE mutations: hematologic disorders (thalassemia, myelodysplastic syndrome), chronic liver diseases, or transfusion history 7

Functional Iron Deficiency

• In chronic inflammatory conditions, elevated hepcidin can cause functional iron deficiency despite normal iron stores 6
• Consider newer markers like reticulocyte hemoglobin content when traditional markers (ferritin and transferrin saturation) give conflicting results 3, 4

Pitfalls in Diagnosis

• Serum ferritin is an acute phase reactant and may be elevated in inflammatory conditions, liver disease, or malignancy, leading to false interpretation of iron status 2, 1
• Transferrin saturation can be affected by diurnal variation; fasting morning samples provide more reliable results 2
• Patients with end-stage renal disease on hemodialysis may have complex iron metabolism requiring specialized interpretation of iron studies 3