Albertine Donker

TSAT/Hepcidin Ratio discriminates TMPRSS6 -related Anemia from IDA 277 8 INTRODUCTION Matriptase 2, a transmembrane serine protease encoded by TMPRSS6, plays a key role in down-regulating hepcidin expression through modulation of the BMP- SMAD pathway when iron stores are low. 1-4 Pathogenic TMPRSS6 variants result in impaired matriptase 2 function, leading to inappropriately high serum hepcidin levels in relation to body iron status. 5,6 Since hepcidin impairs intestinal iron absorption and recycling by inhibiting ferroportin-mediated iron export from enterocytes and macrophages, patients with TMPRSS6 -related IRIDA develop a microcytic anemia with remarkably low transferrin saturation (TSAT<10%), low-to-normal ferritin levels and a poor response to oral iron treatment. 5,7-12 Usually bi-allelic TMPRSS6 variants are found in IRIDA patients, therefore the disease is considered as autosomal recessive. However, anecdotal data are available of phenotypically affected IRIDA patients in whom only a heterozygous TMPRSS6 variant was found, (reviewed in 12 ), corroborating our data. 11 Bi-allelic affected patients typically present in childhood, while mono-allelic affected patients generally present later in life with a milder phenotype regarding hemoglobin (Hb) and mean corpuscular volume (MCV). 11 Diagnosing TMPRSS6 -related IRIDA may be challenging, as the disorder is phenotypically and genotypically heterogeneous. 11 In our case series, time from the identification of anemia to the diagnosis of IRIDA ranged from 1-17 years in the bi- allelic patients and from 1-37 years in the mono-allelic patients. 11 The majority of patients went through extensive diagnostic work-up with invasive diagnostic tests (e.g. gastrointestinal endoscopy and video capsule endoscopy) before IRIDA was diagnosed and effective treatment (primarily parenteral iron) could be initiated. 11 Therefore, we sought to develop a tool to assist clinicians in recognizing and differentiating TMPRSS6 -related IRIDA from other common causes of iron deficiency anemia (IDA), in order to ensure timely diagnosis and prevention of unnecessary invasive diagnostic work-up. Since the cardinal feature of IRIDA is discrepantly high serum hepcidin levels in relation to a low body iron status in general and a low circulating iron pool in particular, the TSAT/hepcidin ratio has been suggested a promising tool in diagnosing IRIDA. 11-14 Our previous case study, comprising 18 IRIDA patients and 20 phenotypically non-affected relatives with or without the relevant TMPRSS6 defect, supported this idea, e.g. the ratio was able to discriminate between