It is good to write up to date things constantly, but let’s talk about Hepcidin, a new and less well known test that may be needed for those who are curious or have academic work.
What is Hepcidin ?
Hepcidin, a small peptide secreted mostly by the liver, plays a central role in the regulation of the iron status in the body.
Experiments on hepcidin have provided quite promising information for understanding the iron metabolism, which is still insufficient.
Many authors suggest that the use of hepcidin can be used as a clinical tool for diagnosis and treatment of many iron-related disorders.
Hepcidin was first discovered as a small bactericidal peptide (defensin and cathelicidin) in human blood ultrafiltrate and urine specimens and was termed the liver-derived antimicrobial peptide (LEAP-1).
Hepcidin name comes from the synthesis site hepatocytes (hep-) and antimicrobial activity (-cidin).
The hepcidin encoding gene (HAMP, 19q13) is excreted in the liver, heart, lungs, brain, spinal cord, intestine, stomach, pancreas, adipocytes, skeletal muscle, testis and macrophages.
Hepcidin genes have also been found in mice, pigs, birds and fish.
Hepcidin has antibacterial (Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus spp., Group B) and antifungal activity (Candida albicans, Aspergillus niger, Aspergillus fumigatus).
This protein is the key regulator of iron level, reducing iron absorption of duodenal enterocytes, iron release from macrophages and iron transfer to placenta.
The main role of hepcidin in iron metabolism has been confirmed by animal models and in vitro studies.
Hepcidin synthesis from hepatocytes can be regulated by iron overload, inflammatory signals, increased erythropoiesis, hypoxia and anemia.
What Are the Mechanisms of Hepcidin’s Effect ?
Hepcidin is known as an iron-regulating hormone. It usually causes a decrease in serum iron.
The mechanism of hepcidin activity depends on ferroportin and hepcidin interaction.
Ferroportin is a known single mammalian cellular iron anchor that is excreted on the surface of reticuloendothelial macrophages, hepatocytes, duodenal enterocytes and placental cells.
Hepcidin rearranges the ferroportin expression postranslationally.
Hepcidin binds to ferroportin and causes internalization and deterioration in endolysosomes, which prevents iron transport through ferroportin.
When the iron stores are enough or high, increased hepcidin synthesis inhibits intestinal iron absorption, release of recovered iron from macrophages and transport through the placenta.
On the other hand, when iron stores are low, hepcidin production is suppressed.
What are the Positive Regulators of Hepcidin Synthesis ?
Hepcidin is not only an iron-regulating hormone, but also an acute phase reactant. This means that its synthesis can be induced by the inflammatory cytokine IL-6.
Some studies show that inflammation and infection rapidly lower serum iron levels, dietary iron absorption and iron release from RE macrophages.
Acts through the IL-6 receptor, and STAT 3 causes dimerization of phospho-STAT 3 and phosphorylation of its translocation to the nucleus. This data confirms that hepcidin may be the pathogen mediator of the chronic disease anemia.
Increase in Iron Deposits
Under normal conditions, the HAMP gene is regulated by the BMP / SMAD and STAT3 pathways.
High-circulating iron-level activated bone morphogenetic proteins (BMPs) bind and complex with type I and II cell serine / threonine kinase BMP receptors in hepatocytes and cause phosphorylation of SMAD protein receptors (R-SMADs).
Phospho-R-SMADs complex with SMAD4 and translocate into the nucleus and activate the transcription of the HAMP gene.
What Are Negative Regulators of Hepcidin Synthesis ?
Hypoxia and Anemia
It has been confirmed that anemia and hypoxia reduce hepcidin synthesis.
Experiments on mice have shown that anemia induced by phenylhydrazine or phlebotomies causes a significant reduction in hepcidin mRNA.
Hypoxia and anemia regulate erythrocyte production through the synthesis of erythropoietin (Epo). Some authors suggest that Epo is a hormone that reduces the expression of hepcidin mRNA.
Erythropoietic activity is a potential inhibitor of hepcidin synthesis, but the specific erythropoietic mediator that regulates hepcidin production is still unknown.
Reduced Iron Deposits
Hemojuvellin in plasma is present in soluble form (s-HJV) and binds to BMPs in response to low serum iron levels and inhibits the BMP / SMAD signal.
Hepcidin in the Pathogenes of Iron and Other Diseases
Hepcidin-related studies have provided important information about the etiology and pathomechanisms of iron metabolism disorders and other diseases.
Hemochromatosis (HH), the most common genetic form of iron overload, is divided into two groups, iron deficiency associated with defective or repressed hepcidin broad and ferroportin disorders.
The first set of diseases consists of four gene mutations: HFE-1, HJV, TfR-2 and HAMP. Patients who are deficient in these genes have a low hepcidin mRNA level when compared to normal individuals.
Hepcidin as an acute phase protein is the main mediator of anemia in inflammatory diseases known as chronic anemia (ACD). The pathogenesis of ACD is associated with reduced iron absorption and impaired mobilization of iron stores.
Individuals with anemia of inflammation characterized by impaired iron absorption, low serum iron and elevated serum ferritin have higher hepcidin levels than healthy individuals.
The higher concentration of serum hepcidin in patients with ACD than in healthy humans can be explained by an increase in IL-6. Interestingly, the relationship between IL-6 and hepcidin levels was also observed in healthy volunteers after acute inflammatory reaction and after injection of lipopolysaccharide.
There is an increase in serum hepcidin levels in many chronic inflammatory diseases such as chronic kidney diseases, thalassemia, deficiency of glucose-6-phosphate dehydrogenase, sickle cell disease, coronary artery disease (CAD) and myelodysplasia.
Hepcidin overexpression has also been demonstrated in clinical trials involving dysmetabolic iron overload syndrome (DIOS). In patients with DIOS, iron absorption is significantly reduced.
Macrophages are highly sensitive when enterocytes are circulating hepcidin-resistant in non-hereditary mild iron-loaded hepatic disease (NHIOD), alcoholic liver disorders, and hepatitis C virus infection (HCV).
Iron overload in hepcidin, NHIOD and HCV patients may be a prognostic and monitoring test. Normalization of the hepcidin concentration may also be indicative of HCV eradication.
Hepcidin as Potential Diagnosis and Therapeutic Vehicle
Discovered by Krause and Park in 2000, hepcidin helped elucidate the pathomechanisms of many diseases as well as opening the way to understanding iron metabolism.
Measurement of hepcidin may be a useful test to distinguish the chronic anemia of chronic inflammation (ACD), which increases hepcidin production, from the anemia of iron deficiency which is reduced by hepcidin level.
One of the most promising promises for the practical application of the hepcidin test is the diagnosis and monitoring of hemochromatosis.
Furthermore, the possible therapeutic value of hepcidin has been investigated. The production of synthetic hepcidin may be useful in the treatment of hemochromatosis and other iron-loading conditions.
In 2008, Ganz and colleagues successfully validated a competitive enzyme linked immunoassay (C-ELISA) assay for human hepcidin measurement. This simple and robust test can be used to determine the physiological and pathological changes in serum or urine hepcidin levels.
This test is expected to be widely used in biochemistry laboratories in the near future.
As a biochemist, I think the opposite. Hepcidin does not add much diagnostic value compared to Ferritin. It can only be used in therapy.
However, much has been said about the biology and function of hepcidin. The signal paths have not yet been drawn. In iron metabolism, there is a need for further studies to identify the role of hepcidin in homeostasis and to use it in the diagnosis and treatment of iron deficiencies.