What laboratory tests should be ordered for the diagnosis and management of hemochromatosis?

Laboratory Tests for Hemochromatosis Diagnosis and Management

For diagnosing hemochromatosis, transferrin saturation (TS) and serum ferritin should be ordered simultaneously as first-line tests, followed by genetic testing for HFE mutations if either is abnormal. 1

Initial Diagnostic Testing

First-Line Tests

• Transferrin Saturation (TS)

  • Abnormal values: >45% in women, >50% in men
  • Sensitivity ≥45% for detecting C282Y homozygotes
  • Should be measured in fasting state for confirmation

• Serum Ferritin

  • Abnormal values: >200 μg/L in women, >300 μg/L in men
  • Correlates with body iron stores
  • Can be falsely elevated in inflammatory conditions, alcoholic liver disease, viral hepatitis, and non-alcoholic fatty liver disease

Second-Line Testing

If either TS or serum ferritin is abnormal:

• Genetic Testing for HFE Mutations
  • Test for C282Y and H63D mutations
  • C282Y homozygosity is the most common genotype causing hemochromatosis
  • C282Y/H63D compound heterozygosity requires further investigation

Liver Disease Assessment

For patients with suspected liver involvement:

• Liver Function Tests

  • ALT and AST
  • Elevated levels with platelet count <200 predict cirrhosis in 80% of C282Y homozygotes 1

• Liver Biopsy (indicated in specific cases)

  • When serum ferritin >1,000 μg/L
  • When liver enzymes are elevated
  • In non-C282Y homozygotes with iron overload
  • When there's clinical evidence of liver disease

• MRI for Hepatic Iron Quantification

  • Useful in cases with unclear cause of hyperferritinemia
  • When biochemical iron overload is present
  • When liver iron staining is positive

Special Considerations

Diagnostic Algorithm

1. Order both TS and serum ferritin simultaneously
2. If either is abnormal (TS ≥45% or ferritin above upper limit of normal), proceed to genetic testing
3. If genetic testing confirms C282Y homozygosity with abnormal iron studies, diagnose HFE hemochromatosis
4. For C282Y/H63D compound heterozygosity with abnormal iron studies, investigate other causes of iron overload

Potential Pitfalls

• False Positives: Ferritin can be elevated in inflammatory conditions without true iron overload 1, 2
• Normal TS with High Ferritin: Should prompt investigation for other causes of hyperferritinemia besides hemochromatosis 2
• Rare Types of Hemochromatosis: Consider non-HFE hemochromatosis if genetic testing is negative despite clinical iron overload 3

Family Screening

• First-degree relatives of patients with HFE-related hemochromatosis should undergo:
  • HFE mutation analysis
  • Iron studies (ferritin and TS)
• For children of an identified proband, test the other parent first 1

Monitoring During Treatment

• Serum Ferritin

  • Monitor every 3-6 months
  • Target level: ≤50 μg/L

• Transferrin Saturation

  • Monitor periodically

• Hemoglobin

  • Monitor during therapeutic phlebotomy to avoid iron deficiency

Additional Tests for Complications

• Fasting Blood Glucose/HbA1c: For diabetes screening
• Cardiac MRI: In patients with signs of heart disease or juvenile hemochromatosis
• Joint Evaluation: For arthropathy assessment

The combination of transferrin saturation and serum ferritin provides excellent diagnostic accuracy, with studies showing both tests have similar reliability in predicting hemochromatosis 4. The unsaturated iron binding capacity (UIBC) can be considered as an alternative to transferrin saturation with equal reliability 4.