Pathogenic TMPRSS6 variants impairing
matriptase-2 function result in inappropriately high
hepcidin levels relative to body
iron status, leading to
iron refractory iron deficiency anemia (IRIDA). As diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the
transferrin saturation (TSAT)/
hepcidin ratio to distinguish IRIDA from multi-causal
iron deficiency anemia (IDA). We included 20 IRIDA patients from a registry for rare inherited
iron disorders and then enrolled 39 controls with IDA due to other causes. Plasma hepcidin-25 levels were measured by standardized
isotope dilution mass spectrometry. IDA controls had not received
iron therapy in the last 3 months and
C-reactive protein levels were <10.0 mg/L. IRIDA patients had significantly lower TSAT/
hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and 16.7%/nM (IQR, 12.0-24.0%/nM), respectively. The area under the curve for the TSAT/
hepcidin ratio was 1.000 with 100% sensitivity and specificity (95% confidence intervals 84-100% and 91-100%, respectively) at an optimal cut-off point of 5.6%/nM. The TSAT/
hepcidin ratio shows excellent performance in discriminating IRIDA from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided that recent
iron therapy and moderate-to-severe
inflammation are absent. These observations warrant further exploration in a broader IDA population.