Transferrin Saturation/Hepcidin ratio discriminates TMPRSS6-related Iron Refractory Iron Deficiency Anemia from Patients with Multi-causal Iron Deficiency Anemia with High Sensitivity and Specificity

Hilde van der Staaij (1,2), Albertine E. Donker (1,2), Jan M. Salemans (3), Lisette A. Mignot (4), Jeanne P. Dieleman (6), Tessel E. Galesloot (7), Marlies Y. Bongers (8,9), Coby M. Laarakkers (1,5), Siem M. Klaver (1,5), Dirk L. Bakkeren (10), Dorine W. Swinkels (1,5)

(1) Radboud university medical center, Translational Metabolic Laboratory , Nijmegen, (2) Máxima Medical Center, Pediatrics, Veldhoven, (3) Máxima Medical Center, Gastroenterology, Veldhoven, (4) Máxima Medical Center, Emergency Department, Veldhoven, (5) Hepcidinanalysis.com, Translational Metabolic Laboratory , Nijmegen, (6) Máxima Medical Center, Máxima MC Academy, Veldhoven, (7) Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, (8) Máxima Medical Center, Gynecology, Veldhoven, (9) Maastricht University Medical Center+, Gynecology, Maastricht, (10) Máxima Medical Center, Clinical Chemistry, Veldhoven

No potential conflicts of interest

Introduction

Pathogenic TMPRSS6 variants impairing matriptase-2 function result in inappropriately high serum hepcidin levels relative to body iron status, leading to the clinical phenotype of Iron Refractory Iron Deficiency Anemia (IRIDA). Due to its genotypical and phenotypical heterogeneity, diagnosing TMPRSS6-related IRIDA can be challenging. Therefore, we assessed the transferrin saturation (TSAT)/hepcidin ratio as a tool to distinguish TMPRSS6-related IRIDA from TMPRSS6-unrelated iron deficiency anemia (IDA).

Methods

TSAT/hepcidin ratios were determined in 21 patients diagnosed with IRIDA due to pathogenic mono- or biallelic TMPRSS6 variants and 39 IDA controls without pathogenic TMPRSS6 variants, all with CRP levels ≤10 mg/L. IDA controls had not received iron therapy in the last 3 months and had no signs of severe renal impairment or chronic liver disease. In all IRIDA patients and IDA controls, serum hepcidin-25 levels were measured by the same standardized isotope dilution mass spectrometry assay.

Results

IRIDA cases showed significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.7 %/nM (range 0.1-9.1 %/nM) and 16.7%/nM (8.0-44.0 %/nM, p<0.0001), respectively. The area under the ROC-curve for the TSAT/hepcidin ratio was 0.99 with a specificity of 100% (95% CI, 93-100%) and a sensitivity of 95% (95% CI, 79-100%) at an optimal cut-off point of 5.9%/nM to differentiate between IRIDA and IDA.

Conclusion

We conclude that the TSAT/hepcidin ratio is an effective tool in distinghuishing TMPRSS6-related IRIDA from multi-causal IDA with high specificity, in which a ratio ≤5.9%/nM strongly indicates the presence of IRIDA, provided inflammatory parameters are low and no iron therapy has been given recently.