Iron Homeostasis for MBBS and MD presentation Purpose

Topic of iron homeostasis equally important for MBBS ,MD, PHD and various other streams , I'm presenting the highly elaborated presentation here.

1. Iron Homeostasis PRESENTER Dr. T ribhuvan Singh PGT 1 LAB MEDICINE Moderator Dr . Garima Chauhan specialist grade 2 BIOCHEMISTRY

2. INTRODUCTION B ackground Distribution of iron Metabolic cycle of iron systemic cellular Disorders of iron metabolism iron deficiency iron overload Lab test of iron status Iron and the microbiome Future areas of research

3. Background Iron plays an essential role in many biochemical processes inside body , and present mainly as two forms in the body incorporated with proteins (A) proteins containing heme iron --- are involved in numerous biological functions such as oxygen binding and transport by hemoglobins , and iron sulfur clusters for oxygen metabolism (catalases, peroxidases), cellular respiration, and electron transport ( cytochromes) and enzymes of the Krebs cycle . (B) Proteins containing nonheme iron -- important for fundamental cellular processes such as DNA synthesis, cell proliferation and differentiation, gene regulation, drug metabolism, and steroid synthesis. i

4. Distribution

5. 1.. Most of the body Fe (3 to 5 g) is found in heme -containing oxygen transport and storage proteins, including hemoglobin (2.5 g) and myoglobin (130 mg). Small amounts ( 150 mg) are incrporated into enzymes. 2.. Most nonheme Fe (1 g in adult men) is stored as ferritin or hemosiderin in macrophages and hepatocytes. Only a very small amount (3 mg) of Fe is bound to the circulating serum protein transferrin. 3 .. Each milliliter of blood contains 0.4 to 0.5 mg of Fe incorporated into Hb . Therefore an adult male body contains approximately 2.5 g of Fe as part of Hb . Cellular Fe in excess of immediate needs is stored as an Fe oxide H emosiderin .

6. .. F erritin is a heteropolymer of 24 subunits of two types, H and L. which assemble to make a hollow spherical shell, which can take up atoms of Fe stored as ferric oxyhydroxide phosphate.The ferroxidase activity of H-ferritin converts Fe2+ to Fe3+ for iron deposition . L (LIVER)– ferritin --predominant in Fe-storing tissues like liver , reticuloendothelial H ( HEART)-ferritin-- is preferentially expressed in cells with a significant antioxidant activity like brain , heart. Physiologically, degradation of ferritin is coupled to the supply of metabolic Fe availability under Fe-limiting conditions. Ferritin is present in nearly all cells of the body and provides a reserve of Fe that is readily available for formation of Hb and other heme proteins. Hemosiderin is an aggregated and partially deproteinized ferritin that is formed when ferritin is partially degraded. hemosiderin is insoluble in aqueous solutions—a difference that has been used traditionally

7. Transferrin is a glycoprotein with an approximate molecular mass of 80 kDa47 and two homologous high-affinity binding sites for ferric ( Fe3+) iron.one for fe3+ and other for Hco3- randomly. Transferrin keeps Fe nonreactive in the circulation and extravascular fluid, and delivers it to cells with transferrin receptors. Cells regulate the intake of transferrin-bound iron by altering the expression of surface transferrin receptor 1 (TfR1).

8. Iron metabolic cycle (1)systemic

9. enterocyte iron enters the body through the diet. Most iron absorption takes place in the duodenum and proximal jejunum. The absorption of iron takes place in different phases. In the luminal phase iron is solubilized and converted from trivalent iron into bivalent iron by duodenal cytochrome B ( DcytB ). mucosal phase iron is bound to the brush border and transported into the mucosal cell by the iron transporter dimetal transporter (DMT1). cellular phase iron is either stored in cellular ferritin or transported directly to the opposite side of the mucosal side . In the last phase of iron absorption Fe2+ is released into the portal circulation by the basolateral cellular exporter ferroportin . Enterocytic iron export requires hephaestin , a multicopper oxidase homologous to ceruloplasmin , which oxidases Fe2+ to Fe3+ for loading onto transferrin. This cellular efflux of iron is inhibited by the peptide hormone hepcidin by binding to ferroportin and subsequent degradation of the ferroportin-hepcidin complex.

10. hepatocyte 1…. serves as the main storage for the iron surplus (most body iron is present in erythrocytes and macrophages ). 2...main producer of hepcidin , largely controls the systemic iron regulation. The signal transduction pathway runs from the membrane to the nucleus, where bone morphogenetic protein (BMP) receptor, the membrane protein hemojuvelin (HJV), the HFE protein and transferrin receptor ( TfR ) -1 and -2, and matriptase-2 play an essential role. 3…Through intracellular pathways, a signal is given to hepcidin transcription. The membrane associated, protease matriptase-2 (encoded by TMPRSS6), detects iron deficiency and blocks hepcidin transcription by cleaving HJV. Defect in TMPRSS6 result in iron refractory iron deficiency anemia (IRIDA). 4 … Hepcidin expression of the hepatocyte is regulated by circulating and stored iron levels, inflammatory stimuli, the erythroid iron demand, and hypoxia, by pathways involving expression of HFE, TFR2, TFR1, HJV and TMPRSS6 genes.

11. Erythroid progenitor cell 1--- In the erythroid progenitor cell, transferrin, with iron molecules, is endocytosed via TfR1. After endocytosis the iron is released from transferrin by acidification, converted from Fe3+ to Fe2+ by the ferroreductase six- transmembrane epithelial antigen of prostate 3 (STEAP3), and transported to the cytosol by DMT1, where it is available mainly for heme synthesis. 2--- In the mitochondria of the erythroid progenitor, heme synthesis and iron- sulfur cluster (Fe-S clusters) synthesis takes place. In the first rate-limiting step of heme synthesis, 5-aminolevulinic acid (ALA) is synthesized from glycine and succinyl -CoA by the enzyme delta- aminolevulinic acid synthase (ALAS2) in the mitochondrial matrix.

12. macrophage The macrophage belongs to the group of reticuloendothelial cells and breaks down senescent red blood cells. During this process iron is released from heme proteins. This iron can either be stored in the macrophage as hemosiderin or ferritin, or may be delivered to the erythroid progenitor as ingredient for new erythrocytes. The iron exporter ferroportin is responsible for the efflux of Fe2+ into the circulation. In both hepatocytes and macrophages this transport requires the multicopper oxidase ceruloplasmin (CP), which oxidases Fe2+ to Fe3+ for loading unto transferrin.

13. (2) Cellular regulation 1--- high cellular iron (Fe) levels, the IRPs are inactive. 2--- Low cellular Fe levels, on the other hand, increase IRP activity. In the latter condition, IRPs bind to the IRE and inhibit mRNA translation (in the case of ferritin and ferroportin) or increase mRNA stability (in case of cellular iron importers such as TfR1 and DMT1). The result is that more Fe enters the cell and less Fe is stored in ferritin or leaves the cell via ferroportin. In conditions of low cellular Fe there is also less synthesis of ALAS-2, the first enzyme in the heme synthesis pathway, and less production of hypoxia-inducible factor (HIF)-2a in kidney fibroblasts, resulting in a decrease in erythropoietin (EPO) production. In the cell, the IRP1 and IRP2 interact with the IRE on mRNA and affect the translation to protein

14. Disorders (1)iron deficiency anemia ****IDA is generally an acquired condition due to blood loss, malabsorption , insufficient iron intake, or combinations of these. ****Some patients with chronic disease are especially vulnerable to develop absolute iron deficiency Ex. patients with gastro-intestinal tumors because of blood loss . **** Patients with advanced chronic kidney disease are also at risk of negative iron balance as a result of reduced dietary intake, impaired absorption from the gut, and increased iron losses. ****An emerging cause of iron deficiency is obesity. It has been largely attributed to functional iron deficiency associated with low-grade inflammation which induces hepcidin levels which reduce iron levels. ***Fe not only plays a key role as an oxygen carrier in the heme group of hemoglobin but is also found in cytochromes and myoglobin.So ****IDA is associated with impaired quality of life, work productivity, aerobic exercise capacity, restless leg syndrome, and fatigue, and there is also a relationship between iron status and depression, and neurocognitive function in children, pregnancy outcomes, and physical exercise performance

15. Stages of ida

16. Anemia of chronic disease ( acd ) 1…ACD is characterized by so-called functional iron deficiency, that is, maldistribution of body iron stores, with ample reticuloendothelial iron contents relative to parenchymal iron stores, with low circulating iron ( hypoferremia ) and subsequent iron–restricted erythropoiesis. The pathophysiology of these ironrelated aspects in ACD can be attributed to cytokine-induced increase in hepcidin synthesis leads to insufficient iron mobilisation . Therefore this is also known as “ hypoferremic anemia with reticuloendothelial siderosis .” 2…ACD also named anemia of inflammation, is an iron distribution disorder. It is often observed in patients with * infectious and inflammatory disease * chronic kidney disease , *inflammatory bowel disease , *chronic heart failure *malignancies , and *hepatic diseases.

17. (2)Iron overload disorders Iron overload disorders are typically insidious, causing progressive and sometimes irreversible tissue damage before clinical symptoms develop These disorders can be categorised based on defect in pathophysiology Disorders of the hepcidin-ferroportin axis– Hereditary hemochromatosis (2) Erythroid maturation—due to scondary iron overload combined with hepcidin downreglation due to gene mutation of GDF15, TWSG1, ERFE . leads to ** ineffective erythropoiesis (i.e., by apoptosis of erythroid precursors ) **failure of erythroid maturation Ex. thalassemia syndromes sideroblastic anemia congenital dyserythropoietic anemias (3) Iron acquisition and transport--- Hypotransferrinemia

18. hereditary hemochromatosis –6 types based on the mutated genes and proteins they encode.

19. Clinical feature and treatment of hh Initial clinical symptoms of tissue Fe overload of these disorders are often nonspecific and vague, for example , fatigue and joint pain. In later stages, disease manifestations may include **diabetes mellitus , ** hypogonadism and ** endocrinopathies -- liver cirrhosis, cardiomyopathy, skin pigmentation ***cirrhotic patients-- increased susceptibility to liver cancer Rx 1--Regular Phlebotomy remains the mainstay of treatment for HH . 2– Iron chelation therepy with deferoxamine , deferasirox , dferiprone

20. Lab test for iron status in adult

21. Iron and the microbiome The intestinal microbiome influences a broad range of metabolic and physiologic processes Most bacteria require iron for growth and survival, and some bacteria have an absolute requirement for iron for survival . Consequently, multiple studies have now shown that iron fortification can alter the microbial profile in the gut, thereby promoting the growth of potentially pathogenic enterobacteria species at the expense of protective lactobacilli and bifidobacteria species . Any consideration of iron supplementation or fortification needs to take into account their effects on the microbiome and potential downstream consequences .

22. Future areas of research Molecules and cellular processes Identification of novel iron-related proteins.  Definition of structure and function relations of proteins in iron metabolism Structural information on many iron-related proteins and membrane.  Intracellular iron trafficking and homeostasis Relations between iron and other metals Some links are widely appreciated (e.g., the copper-dependent iron oxidases,) bu t others require further investigation (e.g., the key iron-transport proteins also transport other metals).   Regulation of genes encoding iron-related proteins understanding of transcriptional regulators and their mechanisms of action .  Factors regulating hepcidin Some pathways are well defined, but others, such as the roles played by HFE and TfR2, require delineation. Effects of subtle changes in iron status Consequences of supraphysiologic iron intake Defining the effects of supplementation of iron-replete individuals has important practical implications.

23. Organ-specific iron homeostasis Different organs and different cell types within organs handle iron differently, and our understanding in this area remains limited .   Prioritization of iron supply to different organs Some tissues are relatively protected from ID or relatively susceptible to iron loading. Understanding the mechanisms underlying this phenomenon is important . Links between iron and the microbiome How iron alters the gut microbiome (and potentially those of other sites) is an important consideration in any studies of supplementation , microbial community composition could affect body iron physiology. Assessing iron status Measurement of subtle changes in iron status and their effects The best methods for measuring small changes in iron status are poorly understood as is the physiologic relevance of these changes. New indicators and combinations of indicators Inflammation Inflammation remains a major influence on key measures of iron status, and how it is taken into account is an important issue. This is increasingly a problem as the level of obesity in the community rises. Genetic profile

24. Researches in Treatments   Oral iron supplements Despite recent advances, more efficient oral iron supplements with fewer adverse side effects are still required.   Iron removal The suite of clinically approved iron chelators remains very limited, and better compounds and more efficient delivery methods are needed.   Personalized medicine and nutrition Contemporary genetic and physiologic knowledge might be used to tailor iron-related treatments (whether they be iron supplementation, iron redistribution, or iron removal) to individuals, specific life stages, or specific clinical conditions more effectively.

25. IRON IN BODY MEANS IMMUNITY ,ENDURANCE, COGNITION ,CONCENTRATION AND LOT OF ENERGY . Thank you