What lab tests indicate iron overload in patients with a history of genetic disorders or frequent blood transfusions?

Laboratory Tests Indicating Iron Overload

The two primary screening tests for iron overload are fasting transferrin saturation and serum ferritin, with transferrin saturation >45% in females or >50% in males plus elevated ferritin (>200 µg/L in females, >300 µg/L in males) indicating likely iron overload requiring further evaluation. 1

Initial Screening Tests

Transferrin Saturation (Primary Screening Test)

• Fasting transferrin saturation is the most important initial screening test for iron overload, particularly in genetic hemochromatosis 1
• Thresholds indicating iron overload:
  • >45% in females 1
  • >50% in males 1
• This test should be performed in the fasting state for accuracy 1

Serum Ferritin (Secondary Screening Test)

• Elevated serum ferritin combined with increased transferrin saturation strongly suggests iron overload 1
• Diagnostic thresholds:
  • >200 µg/L in females 1
  • >300 µg/L in males 1
• Critical caveat: Ferritin is an acute phase reactant and can be falsely elevated by inflammation, infection, malignancy, liver disease, or metabolic syndrome 1, 2, 3

Confirmatory Testing After Abnormal Screening

When Both Tests Are Elevated

• HFE genetic testing for C282Y and H63D mutations should be performed in all patients with unexplained elevated ferritin AND elevated transferrin saturation 1, 4
• This confirms hereditary hemochromatosis as the cause 1

When Only Ferritin Is Elevated (Normal Transferrin Saturation)

• Low or normal transferrin saturation with hyperferritinemia should alert you to secondary causes of iron overload or hyperferritinemia without true iron overload 5
• Before pursuing iron overload workup, exclude common causes of isolated hyperferritinemia:
  • Chronic alcohol consumption 1
  • Inflammation (check CRP) 1
  • Cell necrosis (check AST, ALT, CK) 1
  • Malignancy (ESR, imaging) 1
  • Metabolic syndrome/NAFLD (check blood pressure, BMI, lipids, glucose) 1

Quantitative Iron Assessment in Transfusion-Dependent Patients

Serum Ferritin Monitoring

• In chronically transfused patients (sickle cell disease, thalassemia, myelodysplastic syndrome), serial ferritin should be monitored monthly as an inexpensive trend marker, not as a precise measure of iron burden 2, 3
• Ferritin thresholds in transfused patients:
  • <1500 ng/mL: Generally indicates well-controlled iron burden (90% have liver iron <7 mg/g) 3
  • >2500-3000 ng/mL: Usually indicates significant iron overload (liver iron >10-15 mg/g) 3
  • >4600 ng/mL with poor chelation: Predicts cardiac iron loading in sickle cell disease 3
• In sickle cell disease specifically, inflammation falsely elevates ferritin independent of actual iron burden, making it unreliable as a standalone measure 2, 3

MRI for Tissue Iron Quantification

• MRI for liver iron content (using R2, T2, or R2 methods) should be performed every 1-2 years in chronically transfused patients, as this provides more accurate assessment than ferritin alone** 2, 3
• The same MRI method must be used consistently over time for accurate trending 2
• MRI is particularly helpful for titrating iron chelation therapy regardless of ferritin level 2

Cardiac Iron Assessment

• Routine cardiac T2 MRI screening is NOT recommended for all chronically transfused patients* 2
• Cardiac T2 MRI should be reserved only for high-risk subgroups:*
  • Liver iron content >15 mg/g for ≥2 years 2
  • Evidence of end-organ damage from iron overload 2
  • Cardiac dysfunction 2
• Cardiac iron loading is less common in sickle cell disease compared to thalassemia, making routine screening less valuable 2, 6
• Ferritin and liver iron do not predict cardiac iron loading; cardiac iron develops only with prolonged elevated liver iron concentration 3, 7

Additional Laboratory Markers

Complete Blood Count and Reticulocyte Count

• CBC should be obtained to assess hemoglobin, white blood cell count, and platelet count in patients being evaluated for iron overload disorders 2
• Reticulocyte count reflects bone marrow response and hemolysis 2

Liver Function Tests

• AST and ALT should be checked as part of the initial evaluation, as elevated transaminases may indicate iron-related liver damage 1
• In patients with ferritin >1000 µg/L, elevated AST, hepatomegaly, or age >40 years, liver biopsy may be considered to assess for cirrhosis 1

Clinical Pitfalls to Avoid

• Do not diagnose hemochromatosis based on C282Y homozygosity alone; you must have evidence of increased iron stores (elevated ferritin and transferrin saturation) 1
• Do not rely on ferritin alone in chronically transfused patients, as inflammation falsely elevates values 2, 3
• Do not perform routine cardiac T2 MRI on all transfused patients; reserve for high-risk subgroups to avoid unnecessary cost* 2
• In patients with hyperferritinemia but normal transferrin saturation, investigate secondary causes before assuming iron overload 5
• Monitor for overchelation: If ferritin falls below 1000 mcg/L on two consecutive visits, consider dose reduction of chelation therapy 8
• If ferritin falls below 500 mcg/L, interrupt chelation therapy and continue monthly monitoring 8