Guidelines for Screening and Laboratory Diagnosis of Hereditary Hemochromatosis in Asymptomatic Adults
For asymptomatic adults suspected of having hereditary hemochromatosis (HH), initial screening should be performed using both serum transferrin saturation and ferritin measurements, followed by HFE genetic testing if iron markers are elevated. 1
Initial Screening Tests
Recommended Laboratory Tests
- Transferrin saturation (TS): Primary screening test
- Threshold: >45% in women and >50% in men
- Must be drawn after an overnight fast for accuracy 1
- Serum ferritin: Should be measured simultaneously
Interpretation of Initial Tests
- Both tests should be performed together rather than relying on a single test 2
- If either test is abnormal (TS ≥45% or elevated ferritin), proceed to HFE mutation analysis 2
- Ferritin is an acute phase reactant and can be elevated in inflammatory conditions, liver disease, malignancy, and alcohol consumption, leading to false positives 1
Genetic Testing
When to Perform Genetic Testing
- HFE gene mutation analysis for C282Y and H63D mutations should be performed if iron markers are elevated 1
- C282Y homozygosity accounts for >90% of hereditary hemochromatosis cases 1
Interpretation of Genetic Results
- C282Y homozygotes: Most likely to develop iron overload
- Compound heterozygotes (C282Y/H63D): Can develop iron overload but less commonly
- H63D homozygotes: May develop mild iron overload, but this is much less common than with C282Y homozygosity 1
- C282Y heterozygotes and H63D heterozygotes: Generally not at risk for developing progressive or symptomatic iron overload 2
Additional Testing When Indicated
Liver Assessment
- Liver biopsy should be considered in specific circumstances:
- C282Y homozygotes with serum ferritin >1000 μg/L
- Elevated liver enzymes
- Hepatomegaly
- Age >40 years 1
- A serum ferritin level <1000 μg/L is an accurate predictor for the absence of cirrhosis 2
- A serum ferritin level >1000 μg/L with elevated aminotransferases and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 2
Non-invasive Testing
- MRI quantification of liver iron is a non-invasive method to confirm and quantify iron overload, particularly useful when genetic testing is negative or equivocal 1
Family Screening
Recommendations for Family Screening
- Family screening should be recommended for all first-degree relatives of an identified proband 2
- For ease of testing, both genotype (HFE mutation analysis) and phenotype (ferritin and TS) should be performed simultaneously at a single visit 2
- For children of an identified proband, HFE testing of the other parent is generally recommended 2
Management of Family Members
- If C282Y homozygosity or compound heterozygosity is found in adult relatives of a proband, and if serum ferritin levels are increased, then therapeutic phlebotomy can be initiated 2
- If ferritin level is normal in these patients, then yearly follow-up with iron studies is indicated 2
Important Considerations and Pitfalls
Diagnostic Pitfalls
- Hemochromatosis should not be diagnosed based on C282Y homozygosity alone, as evidence of increased iron stores is required 1
- The lack of information on the natural history of the disease makes it difficult to manage patients with hereditary hemochromatosis 2
- There are no clearly defined criteria to risk-stratify patients into groups more or less likely to develop overt disease 2
Special Populations
- Diagnostic strategies should target high-risk groups such as those with a family history of HH or those with suspected organ involvement 2
- For clinicians who choose to screen, 1-time phenotypic screening of asymptomatic non-Hispanic white men with serum ferritin level and transferrin saturation would have the highest yield 2
By following these guidelines, clinicians can effectively screen for and diagnose hereditary hemochromatosis in asymptomatic adults, allowing for early intervention and prevention of complications such as cirrhosis, diabetes, cardiomyopathy, and arthropathy.