Transferrin Saturation/Hepcidin Ratio Discriminates TMPRSS6-Related Iron Refractory Iron Deficiency Anemia from Patients with Multi-Causal Iron Deficiency Anemia

Abstract

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.

IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology

“…In addition, we also included relatives as family controls in order to gain a better insight into the differences between patients and subjects. Second, for the first time, we determined the TSAT/hepcidin ratio by standardized measurement in all our monoallelic patients to better define whether a patient expresses the IRIDA phenotype [ 24 ]. Age- and gender-specific reference ranges of this ratio are available via our website [ 25 ].…”

“…Iron deficiency anemia (IDA) due to other forms of iron-refractory IDA (e.g., autoimmune gastritis, celiac disease, Helicobacter pylori , and other gastrointestinal infections) were excluded, if applicable. TSAT/hepcidin ratio was used as an additional criterion for IRIDA phenotype confirmation (TSAT/hepcidin ≤ 2.5 percentile in relation to age and gender supporting the diagnosis) [ 3 , 24 , 25 ].…”

Blood cytopenias as manifestations of inherited metabolic diseases: a narrative review

“…In that case, parenteral iron administration should be provided, and if the microcytic anemia improves, genetic testing for mutations in TMPRSS6 should be done [ 11 ]. Transferrin saturation/hepcidin ratio could help diagnose this condition but is not readily available in every biochemistry laboratory [ 12 ].…”

Common Single Nucleotide Polymorphism of TMPRSS6, an Iron Regulation Gene, Associated with Variable Red Blood Cell Indices in Deletional α-Globin Genotypes

“…TMPRSS6 has been described as associated with a type of iron deficiency anaemia (IDA), a condition termed iron-refractory iron deficiency anaemia (IRIDA), which presents highly variable haemoglobin (Hb) levels and mean corpuscular volume (MCV) resulting in microcytic hypochromic anaemia and the iron parameters presents a low transferrin saturation, whereas serum ferritin level is normal and hepcidin is high [ 3 , 4 , 5 ]. A variety of TMPRSS6 defects, including homozygous or compound heterozygous variants, was described previously in the IRIDA patients.…”