Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory

Abstract

TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female. In 7 out of 21 cases DNA sequencing and multiplex ligation dependent probe amplification demonstrated only heterozygous TMPRSS6 variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar TMPRSS6 genotypes. Mono-allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi-allelic patients. Transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA probands than in healthy relatives. Most patients required parenteral iron. Genotype alone was not predictive for the response to oral iron. We conclude that IRIDA is a genotypically and phenotypically heterogeneous disease. The high proportion of female patients and the discrepancy between phenotypes of probands and relatives with the same genotype, suggest a complex interplay between genetic and acquired factors in the pathogenesis of IRIDA. In the absence of inflammation, the TSAT/hepcidin ratio is a promising diagnostic tool, even after iron supplementation has been given. Am. J. Hematol. 91:E482-E490, 2016. © 2016 Wiley Periodicals, Inc.

Figure 1

TSAT/hepcidin ratio in bi‐allelic (1a) and mono‐allelic (1b) affected IRIDA patients and their clinically not affected relatives (2a, 3a, 3b). Patients are defined as having both an IRIDA phenotype (detected after clinical presentation, microcytic anemia, TSAT below the reference range, in the absence of inflammation, not or partially responsive to oral iron) and an IRIDA genotype (a mono‐ or bi‐allelic pathogenic defect in the TMPRSS6 gene). 1. Patients with an IRIDA phenotype; 1a. Probands with bi‐allelic TMPRSS6 defect, n = 11; 1b. Probands with mono‐allelic TMPRSS6 defect, n = 6, and affected relative (mother of patient 17) with mono‐allelic TMPRSS6 defect, n = 1; 2. Relatives without an IRIDA phenotype. 2a. Relatives with bi‐allelic TMPRSS6 defect, n = 2; 3. Relatives without an IRIDA phenotype; 3a. Relatives with mono‐allelic TMPRSS6 defect, n = 14; 3b. Wild‐type TMPRSS6 relatives, n = 4 Patients and relatives with signs of inflammation were excluded from the analysis. Boxes indicate median and interquartile ranges; whiskers describe the range of the data (min–max). *P < 0.05; **P < 0.001 as tested by unpaired t test.