Journal of Health Research and Reviews (in Developing Countries)

: 2019  |  Volume : 6  |  Issue : 2  |  Page : 57--61

A review on iron-refractory iron-deficiency anemia

Sangeetha Thangavelu1, T Varsha2, Vignesh Mariappan3, Vijaya Anand Arumugam2, Preethi Basavaraju2,  
1 Department of Human Genetics and Molecular Biology, Medical Genetics and Epigenetics Laboratory, Bharathiar University, Coimbatore, Tamil Nadu, India
2 Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
3 Central Inter-Disciplinary Research Facility (CIDRF), Sri Balaji Vidyapeeth University, Puducherry, India

Correspondence Address:
Ms. Sangeetha Thangavelu
Department of Human Genetics and Molecular Biology, Medical Genetics and Epigenetics Laboratory, Bharathiar University, Coimbatore - 641 046, Tamil Nadu


Anemia is a common and predominant blood disorder globally, in which the level of hemoglobin or healthy red blood cells are abnormally lower. The most common type of anemia is iron-deficiency anemia (IDA), and the treatment is iron supplementation to the individuals. In some conditions, the iron supplementation does not alter the hemoglobin range, which means the iron given is not taken up by the body of the individual. This condition is found to be iron-refractory IDA (IRIDA). It is the genetic condition, in which the hepcidin, an iron regulatory hormone expression is altered. IRIDA is a rare genetic disorder, which is autosomal recessive in inheritance pattern. Hepcidin alteration blocks the iron absorption, which in turn causes anemic condition. The transmembrane protease serine 6 (TMPRSS6) gene is involved in negative regulation of hepcidin along with the encoding of matriptase-2 enzyme, which is crucial for iron balance in the human body. Matriptase-2 regulates the iron homeostasis by balancing the hepcidin hormone. The genetic polymorphisms in the TMPRSS6 gene result in this a rare type of anemic condition. Therefore, this review particularly focuses on the IRIDA and TMPRSS6 gene, hepcidin, and matriptase-2 enzyme. The review on IRIDA is being found to be important since the clear metabolism of hepcidin and matriptase-2 in iron metabolism are still unclear.

How to cite this article:
Thangavelu S, Varsha T, Mariappan V, Arumugam VA, Basavaraju P. A review on iron-refractory iron-deficiency anemia.J Health Res Rev 2019;6:57-61

How to cite this URL:
Thangavelu S, Varsha T, Mariappan V, Arumugam VA, Basavaraju P. A review on iron-refractory iron-deficiency anemia. J Health Res Rev [serial online] 2019 [cited 2019 Aug 20 ];6:57-61
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Full Text


Iron is important for biological functions such as respiration, energy synthesis, and cell division. In our body, absorption of iron is limited to about 1–2 mg/day, but our body requires about 25 mg/day. It is provided by macrophages through recycling that phagocytose aged red blood cells (RBC). The iron absorption as well as phagocytosis of RBC is regulated by a specific hormone called hepcidin. It maintains total body iron within normal levels, avoiding both iron deficiency and excess.[1] Iron-refractory iron-deficiency anemia (IRIDA) is a rare genetic condition, in which the iron absorption is totally absent as well as the body refuses to respond to the supplemented iron through medications.[2] The prevalence of IRIDA is very less such that it is <1 in 1,00,000 people worldwide.[3] And hence, the literature available for IRIDA in interconnection with transmembrane protease serine 6 (TMPRSS6) gene and hepcidin is very limited, and with the available evidence, this review highlights IRIDA, hepcidin role, and the genetic polymorphisms in the TMPRSS6 gene causing IRIDA.[2]

 Need of the Review

The literature, which has been analyzed for anemia followed by IRIDA in link with TMPRSS6 gene has been found to be constructive. This review has been mainly produced on the aim of giving a clear idea on the link of IRIDA with iron metabolism, hepcidin, and matriptase-2 on the genetic basis.[2] The present literature search for IRIDA as a part of framed hypothesis has been carried out in the PubMed, Scopus, Web of Sciences, and SCI indexed journals, which is limited to humans and keywords such as hepcidin, anemia, hemojuvelin, matriptase-2, and TMPRSS6. In the preliminary stage, the basis of the study relevant to the title was identified. The abstracts were examined for the inclusion of this review.


Anemia has been considered global disorder with complex causes and many associated factors. Even though it is found to be associated with many factors, the major cause is deficiency of iron.[4] The normal production and differentiation of RBC need number of essential nutrients including iron, vitamin B12, and folate. The deficiency in any of the above nutrient will result in decreased synthesis of RBC. Hemoglobin is the iron-containing metalloprotein of RBC, involved in the oxygen transport throughout the body. The improper RBC synthesis causes reduced hemoglobin range resulting in the anemic condition.[5]

The World Health Organization has defined anemia is the condition, in which the hemoglobin level is <12 g/dL in women and 13.5 g/dL in men, whereas in case of newborns, hemoglobin level would be <14 g/dL and in infants 9.5 g/dL.[6],[7] It is a critical health issue worldwide. It majorly affects pregnant women and children. There are currently more than 400 types of anemia identified.[8] Roughly, one-third of the world population is affected by anemia. Approximately, 164 million people are affected worldwide, but only four studies have been reported on the incidence levels.[9]

 Iron-Deficiency Anemia

Iron deficiency anemia (IDA) is the common problem worldwide, which is having the cause typically attributed to acquired improper diet and/or chronic blood loss.[10] Lower iron absorption by the intestine, deficiency in dietary iron intake, increased iron requirements, and iron loss due to bleeding are the major causes of IDA. Iron loss during menstruation is the most common cause of IDA in women. Autoimmune atrophic gastritis and infection with Helicobacter pylori can also cause IDA by decreasing the iron absorption in intestines. In addition to these common causes, IRIDA may be caused due to germline mutations of TMPRSS6.[11] Homozygosity for TMPRSS6 rs855791 C genotype has an active part in protection in women at reproductive age, against IDA, especially in those with menorrhagia.[12]TF, TFR2, and TMPRSS6 polymorphisms are mainly associated with decreased iron levels, but only mutations in TMPRSS6 are genetic risk factors for iron deficiency and IDA.[13]

 Iron-Refractory Iron-Deficiency Anemia

IRIDA is a rare genetic disorder whose inheritance pattern is autosomal recessive.[14] Autosomal recessive is a condition in which two copies of mutated alleles of the gene is required to cause a disease or disorder. It is usually characterized by hypochromic microcytic anemia, reduced transferrin saturation, and improper high levels of the iron-regulating hormone hepcidin. Variants in the TMPRSS6 gene which encodes the type II serine protease matriptase-2 enzyme, a regulator of negative feedback mechanism of hepcidin transcription causes this disease. The germline mutations of TMPRSS6 gene results in a disorder called IRIDA.[8]TMPRSS6 mutations are distributed on the gene and that they completely or partially terminate hepcidin inhibition.[15]

 Genetic Polymorphisms Causing Iron-Refractory Iron-Deficiency Anemia

Transmembrane protease serine 6 and matriptase-2

Loss-of-function mutations in TMPRSS6 results in high hepcidin level that causes IRIDA and also severe anemia.[16] Matriptase-2 is an enzyme which belongs to the type II transmembrane serine protease category, and the TMPRSS6 gene encodes this enzyme. Matriptase-2 was then established to be crucial in iron balance based on the characteristics of IRIDA observed in mice models and also in the human patients with mutations in TMPRSS6 gene. TMPRSS6 is expressed primarily in the liver, and its function is the negative regulation of hepcidin production. From the recent investigations, it has been clear that the function of matriptase-2 is regulation of hepcidin.[17],[18]TMPRSS6 germline mutations in the humans resulted in IRIDA that is completely unsusceptible to treatment with iron orally and gives only partial responsiveness to parental iron therapy.[19] Recently, about 42 distinct TMPRSS6 mutations those distributed entirely in all the distinct domains in extracellular regions have been reported in the humans. A novel case of a female from Japan with IRIDA is the one who carried a novel mutation (K253E) in the CUB (complement factor C1r/C1s, urchin embryonic growth factor, and BMP 1), which is a domain of the TMPRSS6 gene.[20]

The importance of matriptase-2 in controlling iron balance was highlighted by human Genome-Wide Association Studies by identifying common TMPRSS6 mutations associated with abnormal hematological parametric values, including transferrin saturation, erythrocyte mean corpuscular volume, hemoglobin levels, and concentrations of iron in serum.[21],[22],[23]

The TMPRSS6 expression is down-regulated by inflammation ex vivo experiments and experiments inside the living organisms. Bmp-Smad pathway signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems but it does not influence the down-regulation of TMPRSS6 by inflammation in the mice, but the downregulation occurs by a reduction in STAT5 phosphorylation. The positive regulation of TMPRSS6 expression is mediated by STAT5 by binding immediately to a STAT5 element present on the promoter region of TMPRSS6. The inhibition of TMPRSS6 through decreased STAT5 phosphorylation might be another mechanism through which inflammation stimulates the expression of hepcidin to regulate iron balance and immune response.[24]

One frameshift mutation (p. Ala605ProfsX8) and four novel missense mutations (p. Glu114 Lys, p. Leu235Pro, p. Tyr418Cys, and p. Pro765Ala) have been observed in IRIDA patients. Both the catalytic and noncatalytic domains of matriptase-2 are subjected to changes due to this mutation.[25]


Hepcidin usually involves in lowering of serum iron level.[26] The increased production of hepcidin blocks the iron absorption, which results in anemia.[27] Hepcidin regulates the expression of fetoprotein. If the iron storage is high, hepcidin level increases and it prevents the iron absorption in the intestine and the transport of recycled iron across the placenta. If the iron storage is low, the production of hepcidin is suppressed. The gene that encodes hepcidin is HAMP gene present on chromosome 19q13.1.[26] This gene consists of 2637 bp along with 3 exons and 2 introns.[28] Hepcidin is mainly expressed in the liver, whereas its expression can also be observed in the heart, brain, lung, prostate gland, tonsils, salivary gland, and trachea.[29] The precursor for hepcidin is preprohepcidin. It contains 84 amino acids.[26],[29]

 Regulation of Hepcidin

BMP6 and iron not only stimulate the expression of hepcidin but also stimulates TMPRSS6, which acts as a negative controller for the expression of hepcidin. The TMPRSS6 expression modulation can act as a controller of negative feedback mechanism to prevent increasing the excessive hepcidin level by iron to help in maintaining the exact equilibrium of the levels of iron in our system.[30] The increased hepcidin levels in patients with heritable IRIDA are the effect of surplus BMP6/hemojuvelin (Hjv) signaling pathway.[31] The systemic regulation of iron in the human body is influenced by the regulated hepcidin expression.[32]

Matriptase-2 inhibits the activation of hepcidin by splitting membrane Hjv has been demonstrated ex vivo. When it is overexpressed in HeLa cells, matriptase-2 enzyme gets interacted, and it stimulates the membrane Hjv splitting at the cell surface, which results in the generation of Hjv which is soluble in nature which is then discharged inside the cell medium.[33] Moreover, as the response to chronic iron treatment and administration of BMP6 in mice, matriptase-2 levels are also elevated possibly to avoid increased production of hepcidin, suggesting a doubled action of matriptase-2 in the managing the exact systemic iron balance in a reflex action to iron.[30]

The BMP and JAK2/STAT3 signaling pathways mediate the expression of hepcidin.[34] Hepcidin expression in our human body is up-regulated under nonpathological conditions by the iron levels. Recent studies have confirmed the crucial roles of Hjv, hereditary hemochromatosis protein (also known as HFE protein), transferrin receptor 2, and matriptase-2 in the hepcidin regulation process in humans and animal models and also the essential roles of BMP6, neogenin, and BMP receptors (ActRIIA/ALK2/ALK3) in animal models.[35],[36],[37]


IDA is one of the most common predominant blood disorders worldwide. The IRIDA is the improper response of the body toward the iron supplementation, which is given as the treatment for IDA. It is due to certain alterations in matriptase-2 that manages hepcidin hormone, which is the master regulator of iron homeostasis.[38],[39],[40] The pleotropic effect by the TMPRSS6 gene gives the variations in hepcidin concentrations, which in turn alters the iron metabolism.[41],[42] From the available literature, the TMPRSS6, hepcidin, and matriptase-2 have to be taken into consideration while analyzing anemic condition that does not respond to iron supplementation, which may be IRIDA condition. The interlinks between the IRIDA, hepcidin, and matriptase-2 have been well established in this review. The analysis of the signaling pathways of Hjv in IRIDA is yet to be understood.


IRIDA is a new disease entity that must be taken into consideration whenever undergoing a diagnosis of microcytic anemia. From the limited number of studies available, it is clear that TMPRSS6 polymorphisms are responsible for IRIDA. However, a lot remains to be discovered on the biology and functions of hepcidin. The signaling pathways are still has to be delineated.


The authors would like to acknowledge the Authorities of the Institution for providing the moral support in publishing this review.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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