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Lecture 9

Iron Metabolism/Iron Disorders

Primary storage location of iron in the body (1) Reticuloendothelial cells as ferritin and hemosiderin
Components and function of Ferritin Protein consisting of a protein shell and an iron-phosphate-hydroxide core that stores iron as a soluble form. The ferrous (Fe++) form of iron is taken up by the aproferritin molecule and oxidized to ferrous oxide (Fe+++), the form in which it is stored.
Components and function of Hemosiderin Insoluble iron protein complex derived from partial degradation of ferritin aggregates. This aggregated ferritin micelles is a storage form of iron seen most commonly in macrophages.
Ferritin not combined with iron Apoferritin
(T or F) Ferritin levels in circulation is generally proportional to the size of the body reticuloendothelial cell iron store. True.
Transferrin A iron transport molecule that binds 2 Fe atoms.
Where is tranferrin synthesized? (1) Liver (2) Macrophages
Form of iron that binds to transferrin Ferrous oxide (Fe+++)
How does iron enter cells to be incorporated into heme? Transferrin receptor binds 2 transferrins. The receptor-tranferrin-iron complex is endocytosed. The endocytotic vacuole fuses with a lysozyme, where at an acid pH, tranferrin releases iron as ferrous form. The iron is transported to mitochondria.
Dietary forms of iron (1) Inorganic ferric iron (2) Heme iron
(T or F) Heme iron (animal source) is better absorbed than non-heme iron (vegetable source). True.
Portion of the intestine that absorps iron (1) Duodenum (2) Proximal jejunum
How is dietary heme transported across an enterocyte? Heme carrier protein 1 (HCP1)
How is iron separated from dietary heme after absorption? Heme oxygenase
How is non-heme iron or ferric iron transported across an enterocyte? Ferric iron is reduced to ferrous iron by a membrane-bound reductase. Then ferrous iron is transported across the apical memebrane of the enterocyte by a divalent metal transport (DMT1).
How does absorbed dietary iron get transported across the basolateral membrane of an enterocyte? (1) Ferroportin (2) Hephaestin
Where is hepcidin manufactred? Liver
Function of hepcidin The primary regulator of absorption of dietary iron and for release of iron from macrophages. Sinusoidal endothelial and Kuppfer cells exposed to iron-saturated transferrin, bacteria or inflammatory cytokines induce synthesis/secretion of hepcidin.
How does low plasma iron affect hepcidin synthesis and iron homeostasis? Decreases synthesis of hepcidin, which allows increased release of iron into circulation.
How does high plasma iron affect hepcidin synthesis and iron homeostasis? Increases synthesis of hepcidin, which decreases release of iron from enterocytes and macrophages.
Enzyme found in macrophages that catabolize heme and release ferrous iron from phagocytized erythrocytes Heme oxygenase 1
Iron transport molecule that mobilizes iron from macrophages to be incorporated into transferrin Ceruloplasmin
Source of iron stored in the macrophages of liver, bone marrow, and spleen. Phagocytosis of aged erythrocytes and flawed immature red cells accounts for almost all of the sotrage iron found in the macrophages of the liver, bone marrow, and spleen.
Describe the synthesis of [Fe-S] clusters Begins in the mitochondria with elemental sulphur, the cofactor pryridoxal-5-phosphate and a scaffold protein. 2 iron atoms are added to the [Fe-S] cluster and form a single [2Fe-2S] cluster. 2 [2Fe-2S] clusters form a [4Fe-4S]
What are iron regulatory proteins (IRP-1 and IRP-2)? Iron Regulatory Proteins (IRP-1 and IRP-2) are cytoplasmic RNA binding [Fe-S] cluster proteins. They control translation of ferritin and transferrin receptor synthesis by binding to iron-responsive elements (IRE) in RNA.
What is the difference between IRP-1 and IRP-2 (iron regulatory proteins)? IRP-1 switches between two forms: high and low affinity forms. IRP-2 functions like IRP-1, but is either produced or not produced. There are no high or low affinity forms of IRP-2.
Describe the effects of IRP-1 (iron regulatory proteins) on transferrin receptor (TfR1) syntehsis in the setting of high cellular iron. High cellular iron allows [4Fe-4S] cluster formation in IRP-1 (low affinity) which binds to the 3'-IRE of transferrin receptor (TfR1) mRNA, decreasing stability and decreasing translation of TfR1.
Describe the effects of IRP-1 (iron regulatory proteins) on ferritin syntehsis in the setting of high cellular iron. High cellular iron allows [4Fe-4S] cluster formation in IRP-1 (low affinity) which binds to the 5'-IRE of ferritin mRNA, allowing translation into ferritin.
Describe the effects of IRP-1 (iron regulatory proteins) on transferrin receptor (TfR1) syntehsis in the setting of low cellular iron. When cellular Fe is low, [4Fe-4S] clusters fail to form and IRP-1 (high affinity) then binds to the 3'-IRE in tranferrin receptor (TfR1) mRNA, which stabilizes the IRE and increases TfR1 translation.
Describe the effects of IRP-1 (iron regulatory proteins) on ferritin syntehsis in the setting of low cellular iron. When cellular Fe is low, [4Fe-4S] clusters fail to form and IRP-1 (high affinity) then binds to the 5'-IRE of ferritin mRNA blocking translation of ferritin mRNA and decreasing the synthesis of ferritin.
Conditions that create a large demand for iron, which may result in iron deficiency anemia (1) Pregnancy (2) Periods of rapid growth (3) Blood loss due to heavy menstural bleeding (4) Blood loss due to internal bleeding
Signs and symptoms of iron deficiency anemia Fatigue, malaise, shortness of breath, dizziness, and cold sensitivity
Anemia secondary to insufficient dietary iron or from blood loss. Iron deficiency anemia
What type of anemia is characterized by microcytic hypochromic anemia? Iron deficiency anemia
What is the measurement of all iron bound to tranferrin in the body? Serum iron (SI)
What is defined as the concentration of iron needed to saturate the iron binding sites of transferrin? Total iron binding capacity (TIBC)
What approximates the amount of tranferrin in the body? Total iron binding capacity (TIBC)
How is percent of iron saturation? Serum iron (SI) divided by the Total iron binding capacity (TIBC)
Normal range of percent iron saturation? 25-45%
What is the soluble transferrin receptor? It consists of the N-terminal domain proteolytically released from the cell membrane. The soluble form of the receptor circulates in the plasma and reflects the total body mass of cellular transferrin receptor.
MCV and MCHC of microcytic and hypochromic anemia MCV < 80 (microcytic) and MCHC <32 (hypochromic)
What is the biochemical significance of microcytic anemia? Inadequate synthesis of hemoglobin
Is a disorder of iron metabolism in which iron becomes unavailable for use in heme synthesis, resulting in normochromic/normocytic anemia. This type of anemia is usually associated with an underlying disease process. The resolves when the disease resolves Anemia of inflammation or anemia of chronic diseaese
Iron study laboratory results of anemia of chronic anemia Low serum iron, normal or low transferrin, low transferrin saturation, and high serum ferritin
Effect of anemia of inflammation on hepcidin Hepcidin is increased
Pathogenesis of Anemia of Inflammation Inflammatory and infectious disorders release factors suprressing erythropoiesis. IL-1 causes the release of lactoferrin from neutrophils. Lactoferrin binds Fe more avidly than transferrin, shunting Fe to macrophages rather than to erythroid precursors.
Pathogenesis of anemia of renal failure Anemia is due to decreased erythropoietin production and decreased RBC survival.
MCV and MCHC of anemia of renal failure Normocytic-normochromic
Pathogenesis of the hereditary form of sideroblastic anemia X-linked trait with variable expression resulting in decreased activity of ALA synthesis.
Microscopic characteristics of red blood cells in anemia of renal failure Burr cells and normocytic/normochromic red blood cells
Pathogenesis of sideroblastic anemia The incorporation of iron into heme is defective. May be acquired or hereditary.
Treatment for hereditary sideroblastic anemia Pyridoxine (Vitamin B6) supplement
Morphologic characteristics of red blood cells in sideroblastic anemia (1) Ringed sideroblasts (2) Microcytic/hypochromic RBCs (3) Basophilic stippling
Effects on transferrin in sideroblastic anemia Transferrin saturation is elevated (>80%) because iron is not being used.
Effects on serum LDH in sideroblastic anemia Serum LDH is increased indicative of ineffective erythropoiesis.
What type of anemia is the most common and often the earlierst evidence of myelodysplastic syndrome? Acquired sideroblastic anemia
What type of anemia is associated with ringed sideroblasts in the presence of dysplasia of myeloid and megakaryocytic cell lines. Acquired sideroblastic anemia
Pathogenesis of lead poisoning induced sideroblastic anemia Lead inhibits delta-ALA dehydratase, coproporhyrinogen oxidase, and ferrochelatase important for heme synthesis and incorporation of iron. Coproporphyrin and ALA spill into the urine.
Inheritance pattern of Hereditary Hemochromatosis Autosomal recessive, but only 1 in 5 homozygotes develop clinical disease
Gender predilection of hereditary hemochromatosis 10 times more common in males than females
Most common genetic mutation associated with Hereditary Hemochromatosis Mutation of HFE gene
What is HFE? HFE forms a high-affinity complex with the transferrin receptor expressed on the surface of duodenal crypt cells, macrophages, and hepatocytes facilitating ransport of transferrin bound iron.
Gene mutation associated with Hemochromatosis Type 1 HFE gene mutation
What genetic mutation is associated with Hemochromatosis Type 2A? HJV gene that codes for hemojuvelin
What genetic mutation is associated with Hemochromatosis Type 2B? HAMP gene that codes for Hepcidin
What genetic mutation is associated with Hemochromatosis Type 3? TRF2 gene that codes for transferrin receptor 2
What genetic mutation is associated with Hemochromatosis Type 4? SLC40A1 gene that codes for Ferroportin
What are the two major types of HFE mutations associated with Hemochromatosis Type 1? (1) Cys28Tyr (substitution of tyrosine for cysteine - 85-90%) (2) His63Asp (substitution of aspartic acid for histidine - approximately 5%)
What are the recommendations for individuals homozygous for the Cys28Tyr mutation? (1) Regular screening for iron overload (2) Hemochromatosis DNA testing of relatives
A disorder associated with hemojuvelin mutation that causes iron accumulation at an early age (age 15-30yrs). Associated clinical findings include diabetes, impotence, amenorrhea, infertility, and cardiac arrhythmias and heart failure. Juvenile hemochromatosis
A disorder characterized by rapid massive iron buildup in the liver, heart and pancreas of a neonate resulting in stillbirth or death wihtin a few days of birth. Neonatal hemochromatosis
A disorder due to mutations in the ceruloplasmin gene resulting in low serum ceruloplasmin. Aceruloplasminemia
Causes of secondary iron overload (1) Repeated blood transfusionn (2) Ingestion of excessive amounts of dietary or supplmentary iron. Individuals with certain anemias, thalassemia, and siderblastic anemia, or porphyria cutanea tarda are at risk for secondary iron overload.
Created by: UVAPATH4