Albertine Donker

TSAT/Hepcidin Ratio discriminates TMPRSS6 -related Anemia from IDA 291 8 given. 11,12 We hypothesize that in this case another gene or pathway irrespective of hepcidin expression might be involved, explaining the ‘normal’ hepcidin level despite the IRIDA phenotype. 40 Secondly, comorbid conditions could have interfered with the performance of the test. Nevertheless, although factors that have been described to stimulate hepcidin production (i.e. advanced age, high BMI, diabetes mellitus, renal impairment) were more present in the control group, serum hepcidin levels remained very low in our IDA controls. 8 This suggests that iron deficiency in IDA patients seems to be a stronger determinant on net circulating hepcidin levels than these comorbid conditions, as has been demonstrated by others as well. 18,41-43 However, we did not assess the performance of the test in controls who had moderate-to-severe signs of inflammation (CRP >10 mg/L), underlying inflammatory disorders (e.g. malignancy, active IBD), severe kidney impairment (eGFR <90 ml/min/1.73m2) and/or recent iron therapy (<3 months). We expect specificity to be lower in these subgroups, since those conditions are described to increase hepcidin synthesis, which could result in TSAT/hepcidin ratios more resembling those found in IRIDA patients. In addition, due to restricted sample size we could not assess the performance of the TSAT/hepcidin ratio between IRIDA patients of postmenopausal age compared to their IDA counterparts. Moreover, since we did not include children in the IDA control group for ethical reasons, we could also not assess the ratio between children diagnosed with IRIDA and IDA peers. At last, we did not perform genetic testing of TMPRSS6 in our control group, which renders us unable to state with certainty that the controls with ‘unexplained IDA’ had no pathogenic TMPRSS6 variants. Taken together, our findings demonstrated that the TSAT/hepcidin ratio could be a useful tool for differentiating TMPRSS6- related IRIDA from other causes of microcytic anemia early in the diagnostic work-up of IDA. Our observations show that a TSAT/hepcidin ratio ≤5.9%/nM strongly indicates the presence of IRIDA, which could assist clinicians in distinguishing IRIDA from other disorders presenting with IDA, thereby ensuring timely referral for TMPRSS6 testing and early initiation of parenteral iron therapy when TMPRSS6 -related IRIDA has been confirmed after genetic analysis. Moreover, in patients with IDA unresponsive to oral iron treatment in