Using iron studies to predict HFE mutations in New Zealand: implications for laboratory testing

Area of Science:

• Clinical Biochemistry
• Genetics
• Internal Medicine

Background:

• Hereditary hemochromatosis (HH) diagnosis is complicated by non-specific symptoms and confounding factors affecting iron-overload markers.
• Current diagnostic pathways may lack clarity, necessitating evidence-based recommendations for laboratory testing.

Purpose of the Study:

• To correlate iron studies with HFE genotypes to establish evidence-based laboratory testing guidelines for HH in New Zealand.
• To evaluate the predictive value of serum ferritin (SF), transferrin saturation (TS), serum iron (SI), and serum transferrin (ST) for identifying HH mutations.

Main Methods:

• Analysis of HFE genotyping (C282Y, H63D, S65C) and biochemical data from 2388 patients in New Zealand (2007-2013).
• Receiver operator characteristic (ROC) curve analysis to assess the predictive power of iron studies.
• Calculation of sensitivity, specificity, and predictive values for significant iron markers.

Main Results:

• Elevated SF alone prompted HFE genotyping in 62% of cases, with limited C-reactive protein testing to exclude inflammation.
• Transferrin saturation (TS) ≥45% demonstrated the highest sensitivity and specificity for predicting HH mutations.
• A single C282Y homozygote with TS <45% had SF >1000 µg/L, indicating potential HH even with lower TS.

Conclusions:

• Clear guidelines are needed for investigating hyperferritinemia and HH in New Zealand.
• An evidence-based algorithm using TS ≥45%, SF ≥1000 µg/L, and/or family history effectively identified all C282Y homozygotes in the study cohort.