Screening Test for Hereditary Hemochromatosis
The recommended initial screening tests for hereditary hemochromatosis are transferrin saturation and serum ferritin measured simultaneously, followed by HFE genetic testing (C282Y and H63D mutations) if either value is elevated. 1, 2
Initial Screening Approach
Measure both transferrin saturation (TS) and serum ferritin together as the primary screening tests—never rely on a single test alone, as combined interpretation provides optimal diagnostic accuracy 1, 2
Transferrin saturation ≥45% is the primary screening threshold that triggers further evaluation and offers the highest sensitivity for detecting hereditary hemochromatosis 2
Serum ferritin thresholds suggesting increased risk are >300 μg/L in men or >200 μg/L in women 1, 2
When to Proceed to Genetic Testing
Order HFE mutation analysis for C282Y and H63D mutations if either TS ≥45% OR ferritin exceeds the sex-specific threshold 2, 3
The C282Y mutation is present in approximately 90% of patients with hereditary hemochromatosis, with most being homozygous for this mutation 1, 2
Homozygosity for C282Y (C282Y/C282Y) confirms the diagnosis of HFE-related hemochromatosis 2
Who Should Be Screened
First-degree relatives of patients with hereditary hemochromatosis should undergo both phenotypic testing (transferrin saturation and ferritin) and HFE genotyping simultaneously 3, 4
Targeted case-finding is appropriate for individuals with suggestive symptoms (fatigue, arthralgias, hepatomegaly, diabetes, cardiomyopathy, hypogonadism), abnormal liver function tests of unclear etiology, or family history 2, 3
One-time phenotypic screening of asymptomatic non-Hispanic white men has the highest yield for optional screening, given this population has the highest prevalence (0.44% C282Y homozygotes) 1, 3
Routine population-wide screening is NOT recommended due to low penetrance, uncertain benefit of early treatment in asymptomatic genotype-positive individuals, and potential for false positives 2, 3
Critical Pitfalls to Avoid
Serum ferritin can be falsely elevated due to inflammation, chronic liver disease, malignancy, metabolic syndrome, non-alcoholic fatty liver disease, and chronic alcohol consumption—these must be excluded before attributing elevated ferritin to hemochromatosis 2, 3
A normal TS with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis or C282Y/H63D compound heterozygotes, requiring further investigation 2
Transferrin saturation >45% has high sensitivity but lower specificity, potentially identifying secondary iron overload and heterozygotes that require further evaluation 2
Pre-Test Counseling Requirements
- Before ordering genetic testing, discuss with the patient: available treatment (phlebotomy) and its efficacy, costs of testing and ongoing monitoring, implications for insurability and employment, psychological impact of disease labeling, family screening implications, and possibility of uncertain or variant genotypes 1, 2