What labs are used to diagnose and manage hemochromatosis (iron overload disorder)?

Diagnostic and Management Labs for Hemochromatosis

The diagnosis and monitoring of hemochromatosis requires transferrin saturation (TS) and serum ferritin as first-line tests, followed by genetic testing for HFE mutations (C282Y and H63D variants) if either is abnormal (TS ≥45% or ferritin above upper limit of normal). 1

Initial Diagnostic Testing

First-Line Laboratory Tests

• Transferrin saturation (TS)

  • Abnormal values: >45% in women, >50% in men
  • Should be confirmed with a second determination, preferably fasting
  • Sensitivity of ≥45% for detecting C282Y homozygotes

• Serum ferritin

  • Abnormal values: >200 μg/L in women, >300 μg/L in men
  • Provides correlation with body iron stores
  • Less biological variability than TS but can be elevated in inflammatory conditions

Both tests should be performed simultaneously rather than relying on a single test 2, 1. If either test is abnormal, proceed to genetic testing.

Genetic Testing

• Test for C282Y and H63D mutations in the HFE gene
• Most common genotypes causing hemochromatosis:
  • C282Y homozygosity (most common)
  • C282Y/H63D compound heterozygosity (less common)

Additional Testing for Diagnosis and Staging

Liver Function Tests

• ALT and AST (aminotransferases)
• Elevated levels with platelet count <200 predict cirrhosis in 80% of C282Y homozygotes 2

Liver Biopsy

• Not routinely needed for diagnosis since genetic testing became available
• Indications for liver biopsy:
  • Serum ferritin >1,000 μg/L
  • Elevated liver enzymes
  • Non-C282Y homozygotes with iron overload
  • Clinical evidence of liver disease 1

MRI Assessment

• Quantifies hepatic iron concentration
• Useful in:
  • Unclear cause of hyperferritinemia
  • Biochemical iron overload
  • Positive liver iron staining 1
• Cardiac MRI indicated in:
  • Patients with signs of heart disease
  • Juvenile forms of hemochromatosis 1

Monitoring During Treatment

During Initial Iron Depletion

• Hemoglobin levels before each phlebotomy
• Serum ferritin monthly
• Target: ferritin 10-20 μg/L 1

Maintenance Phase

• Serum ferritin every 3-6 months
• Target: ferritin ≤50 μg/L 1
• Transferrin saturation periodically

Family Screening

• All first-degree relatives of patients with HFE-related hemochromatosis should undergo:
  • HFE mutation analysis
  • Iron studies (ferritin and TS) 2, 1
• For children of an identified proband, testing the other parent first is recommended 1

Common Pitfalls and Caveats

• False positive ferritin elevations can occur in:

  • Inflammatory conditions
  • Alcoholic liver disease
  • Viral hepatitis
  • Non-alcoholic fatty liver disease 2, 1

• Risk of iron deficiency during therapeutic phlebotomy:

  • Monitor hemoglobin levels and serum ferritin carefully
  • Avoid excessive phlebotomy that can lead to symptomatic iron deficiency 3

• Comorbid conditions may affect iron parameters:

  • HFE mutations can be cofactors in other liver diseases
  • Additional blood loss (e.g., from varices) can accelerate iron depletion 3

• Unsaturated iron binding capacity (UIBC) can be used as an alternative to transferrin saturation with equal reliability in predicting hemochromatosis 4

By following this systematic approach to laboratory testing for hemochromatosis, clinicians can effectively diagnose, stage, and monitor this common genetic disorder to prevent organ dysfunction and improve outcomes.