Re-evaluating the utility of iron indices in hereditary hemochromatosis genotyping: A retrospective study

•Features the largest North American cohort reported on HFE genotyping.•Determines TSat to be the most effective marker for detecting C282Y homozygosity (over ferritin and ALT).•Discusses laboratory stewardship initiatives for optimizing HFE genetic testing, reducing costs, improving HH patient care. Hereditary hemochromatosis (HH), associated with C282Y or H63D mutations in the HFE gene, is the commonest genetic disorder in Canada. The majority of HH cases are attributable to C282Y homozygosity which can precipitate iron overload and organ damage, but with low penetrance. Elevated transferrin saturation (TSat) and ferritin levels are key biochemical indicators of iron overload in C282Y homozygotes. This retrospective study examined TSat and ferritin levels as predictors of C282Y homozygosity in genotyped patients. This study included 23,432 individuals from Maritime provinces who underwent HFE genotyping from 2009 to 2022. Those with available biomarkers (TSat, ferritin, ALT) were included in the study sample. C282Y and H63D variants were identified based on HFE genotying. Median values for each biomarker were compared across genotypes and their diagnostic performance in predicting C282Y homozygosity evaluated using ROC analysis. 1241 individuals (5.3 %) showed C282Y homozygosity, marking the largest North American study cohort. C282Y homozygotes showed significantly higher median TSat and ferritin levels than wildtypes. TSat showed the best diagnostic performance in detecting C282Y homozygosity (AUC = 0.82, 95 % CI: 0.78–0.85), outperforming ferritin (AUC = 0.54, 95 % CI: 0.50–0.58) and ALT (AUC = 0.59, 95 % CI: 0.56–0.63). TSat thresholds of 32 % (females) and 35 % (males) had a 90 % sensitivity for C282Y homozygosity. Using thresholds of TSat ≤46 % and ferritin ≤370 µg/L (females), and TSat ≤49 % and ferritin ≤703 µg/L (males) reduced the need for genotyping by up to 50 % without missing significant biochemical iron overload cases. Implementing this strategy across 23,432 tests could save $1,701,163 and potentially reduce unnecessary downstream management. Our study suggests significant efficiency savings by implementing an algorithm to reduce unnecessary HFE genotyping and alleviate unwarranted genetic testing anxiety.