What lab parameters are followed for the diagnosis and management of hemochromatosis?

Laboratory Parameters for Hemochromatosis Monitoring

For diagnosis and management of hemochromatosis, transferrin saturation (TS) and serum ferritin should be obtained together as the primary laboratory parameters, with TS ≥45% and elevated ferritin triggering HFE genetic testing. 1

Initial Diagnostic Testing

Primary screening parameters:

• Transferrin saturation (TS): Calculated as serum iron/total iron-binding capacity × 100, with a diagnostic threshold of ≥45% 1
• Serum ferritin: Must be measured simultaneously with TS rather than relying on a single test 1
• Both tests should be obtained together in patients with suggestive symptoms, physical findings, or family history 1

Normal vs. hemochromatosis values: 1

• Serum iron: Normal 60-80 µg/dL; hemochromatosis 150-300 µg/dL
• Transferrin saturation: Normal 20-50%; hemochromatosis 45-100%
• Serum ferritin:
  • Men: Normal 20-200 µg/L; asymptomatic hemochromatosis 150-1000 µg/L; symptomatic 500-6000 µg/L
  • Women: Normal 15-150 µg/L; asymptomatic hemochromatosis 120-1000 µg/L; symptomatic 500-6000 µg/L

Follow-Up Testing After Abnormal Iron Studies

If either TS ≥45% or ferritin is above the upper limit of normal, proceed with: 1, 2

• HFE mutation analysis for C282Y and H63D mutations
• This is the most cost-effective next step, as C282Y mutation is present in approximately 90% of hereditary hemochromatosis patients 2

Assessment of Disease Severity and Hepatic Involvement

Liver function tests are critical for risk stratification: 1

• ALT and AST: Elevated aminotransferases combined with ferritin >1000 µg/L and platelet count <200 predict cirrhosis in 80% of C282Y homozygotes
• Platelet count: <200 is a key predictor of cirrhosis when combined with elevated ferritin and liver enzymes 1

Ferritin as a prognostic marker: 1

• Ferritin <1000 µg/L accurately predicts absence of cirrhosis
• Ferritin >1000 µg/L with elevated ALT/AST and platelets <200 indicates high cirrhosis risk requiring liver biopsy consideration

Monitoring During Treatment

During phlebotomy therapy, monitor: 3

• Hemoglobin levels: To prevent iron deficiency anemia from excessive phlebotomy
• Serum ferritin: Check every 10-12 phlebotomies with target of 50-100 µg/L 2
• Hemoglobin/hematocrit: Before each phlebotomy session 2

Important Caveats and Pitfalls

Ferritin interpretation requires caution: 1

• Ferritin can be falsely elevated due to inflammation, chronic liver disease (alcoholic liver disease, hepatitis B/C, NAFLD), lymphomas, and other inflammatory conditions
• In the general population, iron overload is not the most common cause of elevated ferritin 1
• A normal TS with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis or C282Y/H63D compound heterozygotes 1

Transferrin saturation considerations: 1

• While fasting samples were previously recommended, recent studies show no improvement in sensitivity or specificity for detecting C282Y homozygotes
• Confirm an elevated TS with a second determination 1
• A cutoff of 45% has high sensitivity but lower specificity, potentially identifying secondary iron overload and heterozygotes requiring further evaluation 1

Combined interpretation is essential: 1

• In individuals <35 years, normal ferritin combined with TS <45% has 97% negative predictive value for excluding iron overload
• Never rely on a single test; both TS and ferritin together provide optimal diagnostic accuracy 1