iron metabolism

IRON METABOLISM IN HEALTH AND

DISEASEDr. ANSHUL15/10/2014

1- Introduction2- Intake3- Factors affecting Iron absorption4- Molecules involved in iron metabolism5- Steps of iron absorption6- Iron transport7- Utilization of iron for erythropoesis.8- Disorders of iron metabolism.

1- Introduction• Iron- an important component of all living

organisms.• Metabolic role – Oxygen transport. Energy production by mitochondria (ETC).• regular source- maintain normal health • Storage form – ferritin.

2-Intake • Heme iron and non heme iron.• Only 10- 15% of ingested iron is absorbed

daily.• daily iron requirement – Adult male- 7-10 mg Adult Female- 7-20 mg.

Favored by - Decreased byDietary factors : Dietary factors :

-Increased heme iron. - Decreased heme iron.

- Ferrous iron salts. - Ferric iron salts.

Luminal factors : Luminal factors :

- Acidic pH (gastric acidity) - Alkalies (pancreatic secretions)

-Low molecular weight soluble chelates (vit C, Sugars and amino acids)

-Insoluble iron complexes (phytates, tannates or phosphates)

Systemic factors : Systemic factors :

- Iron defeciency - Iron overload.

- Increased erythropoesis - Decreased erythropoesis.

- Ineffective erythropoesis - Inflammatory disorders.

-Pregnancy, Hypoxia

Iron absorption-

4-Molecules involved in iron metabolism

1- Protein involved in iron transport across cell membranes-

Divalent metal-ion transporter-1(DMIT-1) Ferroportin Transferrin receptor

2- Reductase and oxidase- facilatate movement of iron across cell membrane-

Dudenal cytochrome b (Dcyt b). Ceruloplasmin Hephaestin

4-Molecules involved in iron metabolism

3- Iron transport in circulation and storage Transferrin Ferritin Hemosiderin

4- Protein controls iron homeostasis by regulating all above proteins

Hepcidin

5- Functional compound Hemoglobin, Myoglobin Cytochrome Catalase, Peroxidase.


Divalent Metal Transporter-1 (DMT-1)/ Divalent Cation transporter (DCT-1)

• Protein pump coupled apical tranporter of divalent metal ions.

• Main function- uptake of ferrous form only. Transport iron across the enterocyte apical plasma

membrane. necessary for iron assimilation and utilization by

transferrin or transferrin receptor pathway.• Role in mucosal block as well.


2- Ferroportin • Iron exporter.• present at surface of cells that store or transport iron Basolateral membrane of enterocytes, Hepatocytres Phagocytic cells of RES.• Ferroportin 1- catalyses the exit of divalent metal ions from

epithelial cells into tissues.• Mutation in gene- Autosomal dominant form of iron overload-

HEMOCHROMATOSIS TYPE IV.• Inhibited by Hepcidin- retention of iron in

enterocytes,hepatocytes ,macrophage-- ACD


3- Transferrin receptors

Carrier protein for Transferrin. Import iron in to the cell. Import the iron by internalizing trnsferrin iron complex- receptor mediated

endocytosis

• Two types TfR 1 TfR 2• TfR 1- binds diferric transferrin. - mediates iron delivery to erythroblasts.

• TfR 2- - expressed on hepatocytes and erythroid cells. binds transferrin with low affinity. - mutation causes iron overload.• Truncated portion of TfR shed in blood – measured as serum TfR conc.

Transferrin receptors

• Serum TfR concentration- directly proportional to rate of erythropoesis.

- differentiates iron deficiency anemia from anemia of chronic disorders.

Iron deficiency anemia- Increase in sr TfRAnemia of chronic disorders-decreased in Sr

Tfr.


1- Duodenal cytochrome B ( Dcyt B) • Dihaem protien, member of cytochrome B 561

family of ascorbate dependant reductases.• Site – intestinal brush border and solubilises

dietary iron for absorption by reducing ferric to ferrous iron.

• Rapidly downregulated on receiving large doses of oral iron – molecular mechanism in mucosal block.


2- Hephaestin • Dr. Christopher D Vulpe, university of California in 1999.• Membrane bound homologue of ceruloplasmin, acts as

a multicopper ferroxidase.• Accessory protein required for transfer of iron across

the basolateral membrane and for binding to transferrin,

• Oxidises ferrous to ferric form so that it can be carried by transferrin.

• Location – enterocytes of villus only, not crypt cells.• Deficiency of copper- Iron deficiency anemia.

3-Molecules involves in Iron transport in circulation and storage

1 Transferrin

Transport form of iron. Structure- 678 amino acid glycoprotein. one or two molecules of ferric iron bind to one

molecule of transferrin mono/ diferric forms. Synthesized as apoferritin in liver+ iron

transferrin. Rate of synthesis – inversely proportional to iron

stores.


2- Ferritin

• Discovered by Lanfberger in 1937.• Spherical protein shell- store 4500 iron atoms & transport to area where required. Primary storage compound of iron, readily available

for erythropoesis.• Structure- Multimer (24 subunit polypeptide to form

hollow sphere)• Two monomers L (light type) ferritin H (heavy type) ferritin

• Light type - basic ferritin, contains 174 amino acids. - L monomers have 15 hydrophilic sites which are responsible for binding iron readily and tightly.

- therefore responsible for low turnover of iron and thus suitable for storage.

- liver, spleen and serum.

• Heavy type - acidic ferritin, contains 182 amino acids. - seven hydrophobic sites, takes up and releases iron readily. - heart, kidney, placenta, monocytes, lymphocytes and

erythrocytes.

• Ferrtin level- parallel concentration of iron stores.• Ferritin – acute phase reactant – not reliable indicator


3. Hemosiderin • Heterogeneous aggregate of carbohydrate, lipid ,protein & iron.• formed by degradation of ferritin.

High levels of cellular iron (Ferritin)

Ferritin form aggregates

Taken up by lysosomes and degraded

Hemosiderin

Hemosiderin

• Contains 50 % of iron by weight.• Macrophage of bone marrow, spleen and kupffer

cells of liver.• At lower iron stores - ferritin predominate.• At higher stores- Hemosiderin predominate• Storage form of hemosiderin estimation- Bone

marrow tissue section. (Graded 0-IV)

4- Protein controls iron homeostasis by regulating all above proteins

• HepcidinMaster iron regulating hormone – inhibiting activity of

genes involved in intestinal iron absorption and transport.

Negative regulator of iron absorption/transfer.Hepcidin synthesis controlled by – hypoxia/anaemia Infection /inflammation-

Hepcidin

Infection or inflammation

CYTOKINE IL 6

INCRESED HEPCIDIN SECREATION

1- DECREASE IRON ABSORPTION 2- IRON RETENTION IN MACROPHAGES- as majority of iron for erythropoiesis is recycled

ANEMIA OF CHRONIC DISEASE

5- Functional compound

1- Hemoglobin• Discovered by Hunefeld in 1840.• Max Perutz – molecular structure of hemoglobin by X

ray crystallography in 1959.• Made of 2 pairs of globin chain bearing a heme

molecule.• Heme molecule has central ferrous iron to which

oxygen is attached loosely.• Contains most of the body iron, ideal for carrying

oxygen.• Each molecule of hemoglobin contains 0.34% of iron

by weight. 1 ml of packed red cells contain 1 mg iron.

Structure of hemoglobin molecule

5- Functional compound 2- Myoglobin• Discovered by John Kendrew in 1958.• Monomer, structurally similar to hemoglobin.• Present in all muscles, primary oxygen carrying pigment of

muscle tissue.• Myoglobin in serum – sensitive marker of muscle injury

Structure of myoglobin

5- Steps of iron absorption

• Site- duodenum and jejunum.• 3 stages – 1) reduction and uptake of solubilised iron

through apical membrane. 2) intracellular processing and transport to

basolateral membrane. 3) transfer of iron through basolateral

membrane into portal circulation.

1) Reduction and uptake of solubilised iron through apical membrane-

• D cyt B, ferric reductase, converts ferric to ferrous form.• ferrous form is soluble and has more efficient

mechanism of absorption.• Heme and non heme iron have different mechanisms of

absorption.• Heme iron enters enterocytes via heme receptor and

then degraded to free iron, bilirubin and carbon monoxide by heme oxygenase.

• Ferrous ion uptake is mediated through DMT 1.

2) Intracellular processing of iron :- Iron transported is either stored in the enterocyte-Ferritin or transported across the basolateral membrane.

3) Transfer of iron through basolateral membrane into portal circulation:

- Active process against electric gradient.- Basolateral membrane transporter is ferroportin.- Hephaestin, an accessory protien, transfers iron across the

basolateral membrane and binds to transferrin as it converts ferrous to ferric form.

Iron absorption

6-Iron transport :

• Transferrin transports iron in ferric form and delivers it to various tissues.

• Immature red cells posses high affinity receptors for transferrin .

• Unbound iron leaves plasma rapidly and is taken up non specifically by the tissues.

7-Utilization of iron for erythropoesis :- 80 to 90% of iron entering the cell is taken up by

mitochondria for heme synthesis and rest stored as ferritin.

Body Iron content :

Compartment Iron content Percentage

Hemoglobin 2 gm 67

Storage iron 1 gm 27

Myoglobin 0.13 gm 3.5

Labile pool 0.08 gm 2.2

Tissue iron 0.008 gm 0.2

Transport iron 0.003 gm 0.08

Iron excretion :• Iron loss - faeces, exfoliating skin, urine.• Males -1 mg/day • Mensturating females - 2 mg/day.• Persons with marked iron overload - 4 mg/day

8-Disorders of iron metabolism :• Iron deficiency anemia Etiology:Parasitic infestation- Helminths- tape worm,flukes,round wormBlood loss- menorrhagia, peptic ulcer disease.Dietary iron deficiencyIron malabsorption- Celiac disease, IBD, post surgical reesctionIncreased demand- Menstruation, pregnancy, infancy.- Intravascular hemolysis and hemoglobinuria- Dialysis treatment of chronic renal diseas

• Clinical features :

- fatigubility, irritability, headaches and paraesthesias.- Pica- Restless legs in elderly.- Clinical signs- Pallor, Koilonychia, angular chelitis.

• Lab investigations :- Hb estimation- Peripheral smear study- Bone marrow picture- Serum iron concentration – decreased- TIBC and transferrin saturation – increased- Serum ferritin – decreased- Serum transferrin receptor concentration – increased.

• Management :- Dietary therapy- Iron preparations (oral and parentral)- Blood transfusions.

Disorders of iron storage :

1- Hemosiderosis– Iron overload disorder resulting in accumulation of hemosiderin1 Transfusion hemosiderosis2 Idipathic pulmonary hemosiderosis- Good pasture’s syndrome, Wegener’s granulomatosis

2- Hemochromatosis –• first described by Troiser in France and later by Von

recklingausen.- Clinical presentation- iron induced injury to various organs. Classification – 1) hereditary hemochromatosis. 2) secondary hemochromatosis.

• Causes of secondary hemochromatosis –A) Parentral iron overload.B) Ineffective erythropoesis with increased erythroid activity.C) Increased oral iron intake.D) Congenital atransferrinemia.E) Chronic liver disease.

• Hereditary hemochromatosis : • Pathogenesis –- Hemochromatosis gene, HFE is located on short arm of

chromosome 6.- Crypt cells with mutant HFE lack the facilitating effect on

TfR –dependent iron uptake, thus decreasing the regulatory iron pool in the crypt cell – Excessive iron uptake.

Excessive iron causes toxicity on host tissue by –

- Iron catalysed free radicals reactions- Lipid peroxidation .

- Interaction of reactive oxygen species of iron with DNA lethal injury to DNA, predisposing to HCC.

- Stellate cells located in perisinusoidal space of Disse, undergo numerous phenotypic changes like- , increased collagen synthesis and fibrosis.

• Histopathology- Deposition of hemosiderin in liver, pancreas, myocardium,

pitutary, adrenal gland, thyroid and parathyroid, joints and skin.

- Cirrhosis.- Pancreatic fibrosis.

• Laboratory investigations :- Biochemical determination of hepatic iron concentration. normal ≤ 1000 micro gm/ gm dry weight of liver. Hereditary hemochromatosis – more than 10,000 micro gm/gm. Fibrosis/ cirrhosis – more than 22,000 micro gm/gm dry weight

• Clinical features :- More common in males, evident after 40 years of age.- Hepatomegaly, skin pigmentation, diabetes mellitus and

atypical arthritis.- Hypogonadism - Death due to cirrhosis/ cardiac disease/ hepatocellular

carcinoma.

• Treatment :- Regular phlebotomy.

Disorders of iron transport :1-Congenital atransferrinemia :- Pathogenesis : atransferrinemia decreased delivery of iron to marrow

Marked increase in iron absorption from intestinal mucosa

Decreased hemoglobin synthesis

Severe iron overload Anemia

• 2-Congenital aceruloplasminemia :

- Ceruloplasmin converts ferrous to ferric form. - Ferrous form iron can traverse cell membranes but cannot

bind to transferrin and thus cannot be delivered to erythroblasts.

- Liver, pancreas, CNS and retina.- Dementia, dystonia, dysarthria, DM and retinal degeneration

Other related conditions :• Congenital cataract with hyperferritinemia : Inheritance is AD. - Mutation in iron responsive element (IRE)- unregulated

apoferritin synthesis.- Plasma iron concentration, TIBC and tranferrin saturation are

normal but S.Ferritin concentration is increased. Unregulated synthesis of a protien within lenses causes

adverse colloid osmotic effect congenital cataract.

• Superficial hemosiderosis of CNS :- Due to recurrent subarachnoid hemorrhage with deposition

of iron in meninges.- associated with ataxia and other CNS manifestations.

References:• Mc Kenzie Shirlyn,William J Lynn.Clinical

laboratory haematology,2nd ed,USA;Pearson;2010.pg165-200.

• Bain J Barbara,Bates Imalda,Latten A Michael.Dacie and Lewis Practical haematology,11th ed,China:Elsevier ;2012.p69-125.

• Kumar V, Abbas A K, Fausto N,Aster editors. J C. Robbins and Cotrans pathological basis of disease, 8th edition.USA:Elsevier;2010. p619-645.

• Greer John P. et al .Wintrobes clinical hematology,11th ed,USA;Lippincott Williams and wilkins;2003,p1779-1800.

Health & Medicine

iron metabolism