Haematologic data,iron parameters and molecular findings in two new cases of iron‐refractory iron deficiency anaemia

Matriptase‐2 (Tmprss6), a type II transmembrane serine protease, has an essential role in iron homoeostasis as a hepcidin regulator. Recently, patients with TMPRSS6 mutations and suffering from iron‐refractory iron deficiency anaemia (IRIDA) have been reported. We describe two new cases of IRIDA, one patient of Swiss origin and the second of Italian origin. The first case results from a large deletion of 1054 nucleotides corresponding to an in frame deletion of 30 amino acid residues in the low‐density lipoprotein receptor‐1/‐2 (LDLR‐1/‐2) domains and from a missense mutation in CUB1 (S304L). In the second case, a homozygous G→C mutation in the last nucleotide of exon 15 and which modified the consensus sequence of the 5′ splice donor site of intron 15 (AGgt→ACgt) was identified. Both patients had a high hepcidin level and low serum iron and transferrin saturation compared to age‐matched controls. Continuous perfusion of i.v. iron 4 h/d × 5 d in the first case resulted in a significant rise in haemoglobin. These new cases of IRIDA illustrate the importance of LDLR‐1/‐2 and CUB1 domains in matriptase‐2 function as well as the role of matriptase‐2 in hepcidin regulation. Furthermore a deletional form of TMPRSS6 (in LDLR‐1/‐2 domains) resulting in IRIDA is described for the first time. These cases reinforce the belief that patients suffering from IRIDA have no specific geographical or ethnic distribution and are sporadic secondary to different mutations of the matriptase‐2 gene.     

Mitochondrial content and hepcidin are increased in obese pregnant mothers

Objective: Maternal obesity is characterized by systemic low-grade inflammation and oxidative stress (OxS) with the contribution of fetal sex dimorphism. We recently described increased mitochondrial content (mtDNA) in placentas of obese pregnancies. Here, we quantify mtDNA and hepcidin as indexes of OxS and systemic inflammation in the obese maternal circulation.

Methods: Forty-one pregnant women were enrolled at elective cesarean section: 16 were normal weight (NW) and 25 were obese (OB). Obese women were further classified according to the presence/absence of maternal gestational diabetes mellitus (GDM); [OB/GDM(–)]: n?=?15, [OB/GDM(+)]: n?=?10. mtDNA and hepcidin were evaluated in blood (real-time PCR) and plasma (ELISA).

Results: mtDNA and hepcidin levels were significantly increased in OB/GDM(–) versus NW, significantly correlating with pregestational BMI. Male/female (M/F) ratio was equal in study groups, and overall F-carrying pregnancies showed significantly higher mtDNA and hepcidin levels than M-carrying pregnancies both in obese and normal weight mothers.

Conclusions: Our results indicate a potential compensatory mechanism to increased obesity-related OxS and inflammation, indicated by the higher hepcidin levels found in obese mothers. Increased placental mitochondrial biogenesis, due to lipotoxic environment, may account for the greater mtDNA amount released in maternal circulation. This increase is namely related to F-carrying pregnancies, suggesting a gender-specific placental response.     

Extrahepatic hepcidin production: The intriguing outcomes of recent years

Hepcidin is the hyposideremic hormone regulating iron metabolism. It is a defensin-like disulfide-bonded peptide with antimicrobial activity. The main site of hepcidin production is the liver where its synthesis is modulated by iron, inflammation and erythropoietic signaling. However, hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs. This review highlights the presence of peripheral hepcidin and its potential functions. Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies.     

The management of anaemia and haematinic deficiencies in pregnancy and post‐partum

Anaemia is one of the most common disorders in the world (24·8% of the world population) (de Benoist 2008) and affects patients of all ages and ethnic origins. Underlying causes and prevalences vary by age group and socioeconomic background, but pregnant women everywhere are at high risk of anaemia, the vast majority of cases being due to iron deficiency. One in four pregnant women in Europe are thought to have iron deficiency anaemia (Daru et al., March 2016), whereas in parts of Africa, where hookworm infestation is common, this has been estimated to be as high as 38% (Stevens et al., 2013) to 50% (Bah et al., June 2017). Women of menstruating age are rarely iron replete (Low et al., 18 April 2016) and then enter pregnancy, which carries a major negative iron balance (Bentley, October 1985). Despite a good understanding of the causes of anaemia in pregnancy, there is still uncertainty about how best this should be investigated, prevented and managed. This reflects the limitations of laboratory tests, as well as the poor understanding of how best to replace iron, given the complex physiological mechanisms of iron absorption and distribution. A strategy for iron replacement in a population of anaemic pregnant women needs to be developed not only based on what is biologically and clinically most appropriate but also in the context of each organisation's delivery of care structure, taking into consideration aspects of cost effectiveness. For this reason, management algorithms must be adapted locally, ensuring they meet basic clinical imperatives.     

Role of interleukin-6 in hypoxic regulation of intestinal iron absorption

The regulation of intestinal iron absorption is not fully understood. Hepcidin, a liver-produced peptide, has recently been identified as a negative regulator of iron absorption in various conditions associated with altered iron metabolism (e.g. inflammation, anaemia, hypoxia). It is not clear whether these perturbants share a common signalling pathway. In this study, the importance of the cytokine interleukin-6 (IL-6) was investigated in the hypoxic mouse model. Hypoxia was associated with increased levels of circulating IL-6, decreased liver hepcidin mRNA and increased iron absorption (especially MT). A significant positive correlation existed between the total iron uptake and IL-6 levels in circulation. IL-6 per se, though inducing hepcidin mRNA, failed to affect basal iron absorption. The adaptive response to absorption following the hypoxic exposure was, however, more prominent if mice had been treated concurrently with IL-6. This enhancement in absorption occurred even though hepcidin mRNA was not significantly changed. Similar prominent responses were seen with both human and mouse IL-6. Anti-IL-6 antiserum normalised iron absorption in mice exposed to hypoxia, because of a reduction in the MT. These data indicate that IL-6 can influence iron absorption (especially MT) during the hypoxic exposure, but via a mechanism independent of hepcidin.     

Essential but toxic: controlling the flux of iron in the body

Iron is an essential nutrient, but, because it is toxic when present in excess, its levels in the body are tightly controlled. This regulation is affected by controlling the release of iron into the plasma. Most iron enters the plasma from macrophages, which recycle iron from senescent erythrocytes, but dietary iron absorption and the release of hepatocyte storage iron are other major sources. Cellular iron export is mediated by the membrane iron transporter ferroportin 1, in conjunction with an iron oxidase. Hephaestin provides this oxidase activity in the intestine, whereas ceruloplasmin is the oxidase used by most other tissues. The liver-derived peptide hepcidin binds to ferroportin 1 and removes it from the cell surface, thus reducing iron donation to the plasma. The levels of hepcidin, in turn, reflect body iron requirements. At the cellular level, ferroportin 1 can also be regulated independently of hepcidin by hypoxia-inducible factors and the iron regulatory proteins. The hepcidin-ferroportin axis plays a critical role in regulating body iron homeostasis.