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,

Hepcidin and Anemia: A Tight Relationship

“…A spectrum of conditions can be envisaged ranging from classic severe IRIDA due to homozygous or compound heterozygous TMPRSS6 mutations to increased susceptibility to iron deficiency conferred by single mutations/polymorphic changes. One approach proposed to predict classic IRIDA is hepcidin normalization on other iron parameters, as ratios transferrin saturation (Tsat)/log hepcidin or Tsat/log Ferritin (Donker et al, 2016). According to other authors, most patients with a severe IRIDA phenotype have biallelic TMPRSS6 mutations and, when unidentified, the second allele may be genetically occult (Heeney et al, 2018).…”

Standardized serum hepcidin values in Dutch children: Set point relative to body iron changes during childhood

“…Examples include (a) evaluation of suspected IRIDA 5,6,8 ; (b) diagnosis of concomitant ID in patients with anemia of inflammation 9 ; (c) prediction of responsiveness to oral iron therapy and guiding iron treatment under conditions of competing signals (anemia, ID, inflammation) [10][11][12] ;…”

Systematic evaluation of paediatric cohort with iron refractory iron deficiency anaemia (IRIDA) phenotype reveals multiple TMPRSS6 gene variations

“…However, GWAS are needed in a large sample of our population to identify and define the frequency of TMPRSS6 and other iron‐related gene polymorphisms. Moreover, queries arising from our study, such as why all of the cases affected with genetic variations are male in present study, although a recent report has shown that more females were affected in an IRIDA cohort (Donker et al , ), needs to be investigated in larger prospective studies. Do other genetic factors related with ethnicity in our region affect iron‐related genes or are some trans‐acting genes or factor(s) on the X‐chromosome responsible for this phenotype?…”