Is Serum Hepcidin a Useful Diagnostic Test for Iron Deficiency?

Iron deficiency remains the commonest blood disorder worldwide. Hepcidin is a key regulator of iron homeostasis. In iron depletion, decreased hepcidin facilitates increased iron absorption and recycling. Hepcidin is detectable in whole blood, serum & urine, and although assays have been developed, the utility and clinically appropriate cutoffs for diagnosis of iron deficiency remain to be established. Blood donors are at particular risk of iron deficiency, yet early diagnosis remains challenging in this setting; thus donors are an ideal population in which to evaluate a new diagnostic test of iron deficiency. We evaluated hepcidin as a diagnostic test of iron deficiency in female blood donors.

Subjects: Premenopausal, non-anemic females accepted for whole blood donation by the Australian Red Cross Blood Service, not taking iron supplements and with no history of hemochromatosis. Iron status assessment: Serum ferritin (chemiluminescence), soluble transferrin receptor (sTfR) (immunoturbidometry) and serum hepcidin (competitive ELISA). Analysis: Diagnostic utility of hepcidin, compared with ‘gold standards’ ferritin, sTfR and sTfR/log(ferritin) index, was evaluated by Area under Receiver Operating Characteristic curves (AUC^ROC). Potential hepcidin cutoffs were identified, and their sensitivities and specificities evaluated.

We recruited 261 donors: 22.6% had ferritin<15ng/mL, 10.3% had sTfR>4.4mg/mL, and 20.3% had sTfR/log(ferritin) index>3.2. The 95% range of hepcidin values was <5.4-175.0ng/mL (overall); 9.3–203.0ng/mL (if ferritin≥15ng/mL); and 8.1–198.5ng/mL (if sTfR/log(ferritin)index≤3.2). By linear regression, log(hepcidin) was associated with log(ferritin) (coefficient +1.08, P<0.001); log(sTfR) (coefficient -2.02, P<-0.001) and log(sTfR/ferritin index) (coefficient -1.58, P<0.001). The AUC^ROC for hepcidin, compared with sTfR/log(ferritin) index>3.2 was 0.89, compared with ferritin<15ng/mL was 0.87 and compared with sTfR>4.4mg/mL was 0.81. An undetectable hepcidin (<5.4ng/mL) had sensitivity and specificity of 32.2% and 99.9% respectively for identification of sTfR/log(ferritin) index>3.2; hepcidin<8.1ng/mL had sensitivity and specificity of 41.5% and 97.5% respectively, and hepcidin<20ng/mL had sensitivity and specificity 74.6% and 83.2% respectively.

Hepcidin shows promise as a diagnostic test for iron deficiency. Further work is needed to select suitable cutoffs for this assay, however a cutoff of <8.1ng/mL seems to accurately identify normal subjects, whilst <20ng/mL offers a balance between appropriate identification of cases and normal subjects. Hepcidin may become a valuable clinical index of iron status. Rapid diagnosis of iron deficiency with point of care whole blood or urine hepcidin assays may be achievable and useful in various settings, including blood donation. Prevention of donor iron deficiency is a high priority for the Australian Red Cross Blood Service and is being addressed through a comprehensive strategy.

Westerman:Intrinsic Life Sciences: Employment, Membership on an entity's Board of Directors or advisory committees. Nemeth:Intrinsic Life Sciences: Employment, Membership on an entity's Board of Directors or advisory committees. Ganz:Intrinsic Life Sciences: Employment, Membership on an entity's Board of Directors or advisory committees.