Iron Metabolism_Level II_19 June 2008 Students

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Human Iron metabolism

Heme and IronOutline

Heme metabolism is an important metabolic process because many important proteins

contain hemeas a prosthetic group. When these hemoproteins turn over, the heme is notsalvaged, but is degraded. New heme is synthesized for their replacements.

Heme is a member of a family of compounds calledporphyrins.

Heme synthesis occurs partly in the mitochondria and partly in the cytoplasm. Theprocess begins in the mitochondria because one of the precursors is found only there.Since this reaction is regulated in part by the concentration of heme, the final step (which

produces the heme) is also mitochondrial. Most of the intermediate steps are cytoplasmic.

Summary of regulation of heme synthesis.

Porphyrias are defects in porphyrin metabolism.

Heme degradationis an important metabolic process.

Iron metabolism is shaped by iron's status as an essential nutrient for which there is nomechanism for excreting any excesses that may accumulate in the body.

Iron absorption is affected by the form in which iron is presented to the digestive tract,

and inorganic iron ions change oxidation state during the absorption process.

Regulation of iron uptake occurs at the basal membrane of the intestinal mucosal cells.These cells make an iron-binding protein, apoferritin.

Iron transport and storage involve changes of oxidation state. The capacity of the plasma

to transport iron is of clinical interest. Excess stored iron can cause pathology.
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Human beings use 20 mg of iron each day for the production of new red blood cells,

much of which is recycled from old red blood cells.

Human iron metabolism is the set of chemical reactions maintaining humanhomeostasis ofiron. Iron is an essential element for most life on Earth, including human

beings. The control of this necessary but potentiallytoxic substance is an important partof many aspects of human healthanddisease.Hematologists have been especially

interested in the system of iron metabolismbecause iron is essential to red blood cells.Most of thehuman body's iron is contained in red blood cells' hemoglobin, and iron

deficiency is the most common cause ofanemia.

Understanding this system is also important for understanding diseases ofiron overload.

Recent discoveries in the field have shed new light on how humans control the level ofiron in their bodies and created new understanding of the mechanisms of several diseases.

Importance of iron regulation

Structure ofHeme b; "Fe" is the chemical symbol of iron.
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Heme and Iron Metabolism: Role in Cerebral HemorrhageKenneth R Wagner, Frank R Sharp, Timothy D Ardizzone, Aigang Lu and Joseph F Clark

Journal of Cerebral Blood flow & Metabolism, 2008

Increased intracellular iron levels act at the posttranscriptional level through iron

response proteins (IRPs) to stabilize ferritin mRNA, thereby promoting iron storageand simultaneously destabilizing transferrin receptor mRNA to decrease iron (FE)

uptake. Diagram also depicts heme synthesis regulated through 5-aminolevulinicacid synthase. Heme degradation occurs by constitutive and inducible heme

oxygenase (HO) isoforms, HO-2 and HO-1, respectively. HO-2 and HO-1 degradationof heme generates biologically active products including iron, carbon monoxide (CO),

and bilirubin from biliverdin by biliverdin reductase (BvR). Heme acts directly ondelta-5-aminolevulinic acid synthase ( ALA-S)1 to reduce synthesis and on heme

oxygenase to stimulate its degradation. Heme acts indirectly through iron release

from HO and IRPs to affect ferritin and transferrin receptor synthesis. SDH, succinatedehydrogenase; ALA = delta amino levulinic acid; NADP, nicotinamide adenine

dinucleotide phosphate, CoA, coenzyme A; cGMP, cyclic guanosine monophosphate;NOS, nitric oxide synthase.


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Iron is an absolute requirement for most forms of life, including humans and most

bacterialspecies. Becauseplants and animalsall use iron, iron can be found in a widevariety of food sources.

Iron is essential to life, because of its unique ability to serve as both anelectron donor

andacceptor.

Iron can also be potentially toxic. Its ability to donate and accept electrons means that ifiron is free within the cell, it can catalyzethe conversion ofhydrogen peroxide intofree

radicals. Free radicals can cause damage to a wide variety of cellular structures, and

ultimately kill the cell. To prevent that kind of damage, all life forms that use iron bind

the iron atoms toproteins. That allows the cells to use the benefits of iron, but also limit

its ability to do harm.

[1]

The most important group of iron-binding proteins contain the hememolecules, all of

which contain iron at their centers. Humans and most bacteria use variants ofhemetocarry out redox reactions and electron transportprocesses. These reactions and processes

are required foroxidative phosphorylation. That process is the principal source of energy

for human cells; without it, our cells would die.

Humans also use iron in the hemoglobin ofred blood cells, in order to transport oxygenfrom the lungs to the tissues and to export carbon dioxide back to the lungs. Iron is also

an essential component ofmyoglobin to store oxygen in muscle cells.

The human body needs iron for oxygen transport. That oxygen is required for the

production and survival of all cells in our bodies. Human bodies tightly regulate ironabsorption and recycling. Iron is such an essential element of human life, in fact, that

humans have no physiologic regulatory mechanism forexcreting iron. Most humans

prevent iron overloadsolely by regulating iron absorption. Those who cannot regulateabsorption well enough get disorders ofiron overload. In these diseases, the toxicity of

iron starts overwhelming the body's ability to bind and store it. [2]

Bacterial protection

A proper iron metabolism protects againstbacterial infection. If bacteria are to survive,then they must get iron from the environment. Disease-causing bacteria do this in many

ways, including releasing iron-binding molecules calledsiderophores and thenreabsorbing them to recover iron, or scavenging iron from hemoglobin and transferrin.

The harder they have to work to get iron, the greater a metabolic price they must pay.

That means that iron-deprived bacteria reproduce more slowly. So our control of ironlevels appears to be an important defense against bacterial infection. People with
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increased amounts of iron, like people withhemochromatosis, are more susceptible to

bacterial infection. [3]

Although this mechanism is an elegant response to short-term bacterial infection, it cancause problems when inflammation goes on for longer. Since the liver produces hepcidin

in response to inflammatory cytokines, hepcidin levels can increase as the result of non-bacterial sources of inflammation, like viral infection, cancer, auto-immune diseases or

other chronic diseases. When this occurs, the sequestration of iron appears to be themajor cause of the syndrome ofanemia of chronic disease, in which not enough iron is

available to produce an adequate number ofhemoglobin-containing red blood cells.[4]

Body iron stores

1918 illustration of blood cell production in thebone marrow. In iron deficiency, the

bone marrow produces fewer blood cells, and as the deficiency gets worse, the cells

become smaller.
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Hemosiderosis, Hemochromatosis: Normal Iron

MetabolismImage ID: 1356


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Reasons for iron deficiency

Iron is an important topic inprenatal care because women can sometimes become iron-deficient from the increased iron demands of pregnancy.

Functional or actual iron deficiencycan result from a variety of causes, explained in more

detail in the article dedicated to this topic. These causes can be grouped into several

categories:

Increased demand for iron, which the diet cannot accommodate.

Increased loss of iron (usually through loss of blood).

Nutritional deficiency. This can either be the result of failure to eat iron-

containing foods, or eating a diet heavy in food that reduces the absorption ofiron, or both.

Inability to absorb iron because of damage to the intestinal lining. Examples of

causes of this kind of damage include surgery involving the duodenum, ordiseases like Crohn's orceliac sprue which severely reduce the surface area

available for absorption.

Inflammation leading to hepcidin-induced restriction on iron release from

enterocytes (see below).

The possibility of too much iron

The body is able to substantially reduce the amount of iron it absorbs across the mucosa.It does not seem to be able to entirely shut down the iron transport process. Also, in

situations where excess iron damages the intestinal lining itself (for instance, when

children eat a large quantity of iron tablets produced for adult consumption), even more

iron can enter the bloodstream and cause a potentially deadly syndrome ofironintoxication. Large amounts of free iron in the circulation will cause damage to critical

cells in the liver, the heart and other metabolically active organs.
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Iron toxicity results when the amount of circulating iron exceeds the amount of

transferrin available to bind it, but the body is able to vigorously regulate its iron uptake.

Thus, iron toxicity from ingestion is usually the result of extraordinary circumstances likeiron tablet overdose[8] rather than variations in diet. Iron toxicity is usually the result of

more chronic iron overload syndromes associated with genetic diseases, repeated

transfusions or other causes.

Diseases of iron regulation

The exact mechanisms of most of the various forms of adult hemochromatosis, which

make up most of the geneticiron overload disorders, remain unsolved. So while

researchers have been able to identify genetic mutations causing several adult variants ofhemochromatosis, they now must turn their attention to the normal function of these

mutated genes.

Haemochromatosis (American spelling hemochromatosis), is a hereditary disease

characterized by excessive absorption of dietary ironresulting in a pathologic increase intotal body iron stores. Humans, like virtually all animals, have no means to excrete

excess iron.[1] Excess iron accumulates in tissues and organs disrupting their normal

function. The most susceptible organs include the liver,adrenal glands, theheart and thepancreas; patients can present with cirrhosis, adrenal insufficiency, heart failure or

diabetes.[2] The hereditary form of the disease is most common among those of Northern

European ancestry, in particular those of British descent.[3]

"Haemochromatosis" less often refers to the condition of iron overload as a consequenceof multiple transfusions. A more preferred term in the United States for transfusional iron

overload is hemosiderosis. Those with hereditary anemias such as beta-thalassaemia

major, sickle cell anemia and Diamond-Blackfan anemia who require regular transfusionsof red blood cells are all at risk for developing life-threatening iron overload. Older

patients with various forms of bone marrow failure such as with myelodysplastic

syndrome who become transfusion-dependent are also at risk for iron overload.

Chemistry

Serum transferrin and transferrin saturationTransferrinbinds iron and isresponsible for iron transport in the blood. Measuring transferrin provides a crude

measure of iron stores in the body. Saturation values in excess of 62% are recognized as a

threshold for further evaluation of haemochrmoatosis.

Serum Ferritin- Ferritin, a protein synthesized by the liver is the primary form of ironstorage within cells and tissues. Measuring ferritin provides another crude estimate of

whole body iron stores though many conditions notably inflammation can elevate serum

ferritin. Normal values for males are 12-300 ng/ml (nanograms per milliliter) and for
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female, 12-150 ng/ml. Other blood tests routinely performed:blood count,renal function,

liver enzymes, electrolytes,glucose (and/or an oral glucose tolerance test (OGTT)).

Functional testing

Based on the history, the doctormight consider specific tests to monitor organdysfunction, such as an echocardiogramforheart failure, or blood glucose monitoring forpatients with haemochromatosisdiabetes.

Transferrin

Transferrin

n

Transferrin is ablood plasmaproteinforironion delivery. Transferrin is aglycoprotein,which binds iron very tightly but reversibly. Although iron bound to transferrin is less

than 0.1% (4 mg) of the total body iron, dynamically it is the most important iron pool,

with the highest rate of turnover (25 mg/24 h). Transferrin has a molecular weight of

around 80 kiloDaltons and contains 2 specific high affinity Fe(III) binding sites. Theaffinity of transferrin for Fe(III) is extremely high (10^23 M^-1 at pH 7.4) but decreases

progressively with decreasing pH below neutrality.

When not bound to iron, it is known as "apotransferrin" (see also apoprotein).

Transport mechanism
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When a transferrin protein loaded with iron encounters a transferrin receptoron the

surface of a cell(importantly, to erythroid precursors in the bone marrow), it binds to it

and is consequently transported into the cell in a vesicle. The H+ ATPase of the cell willdecrease the pH of the vesicle, causing transferrin to release its iron ions. The receptor

with its ligand bound to it is then transported through the endocytic cycleback to the cell

surface, ready for another round of iron uptake. Each transferrin molecule has the abilityto carry two iron ions in the ferricform (Fe3+).

Immune system

Transferrin is also associated with the innate immune system. Transferrin is found in the

mucosa and binds iron, thus creating an environment low in free iron, where few bacteriaare able to survive. The levels of transferrin decreases in inflammation [1], seeming

contradictory to its function.

A decrease in the amount of transferrin would result in hemosiderin in the liver.

Pathology

A deficiency is associated with atransferrinemia.

References

1. ^ Andrews NC. Disorders of iron metabolism.New England journal of Medicine.

341(26):1986-1995. December 23, 1999. Also, see related correspondence,published in NEJM 342(17):1293-1294, Apr 27, 2000.

2. ^ Schrier SL and Bacon BR. Iron overload syndromes other than hereditaryhematochromatosis. Up-to-Date (Subscription required). Accessed December

2005.3. ^ Schrier SL. Regulation of iron balance. Up-to-Date (Subscription required).

Accessed December 2005.

4. ^ Andrews NC. Disorders of iron metabolism.New England Journal ofMedicine. Related correspondence, published in NEJM 342(17):1293-1294, Apr

27, 2000.

5. ^ Fleming RE and Bacon BR. Orchestration of iron homeostasis.New EnglandJournal of Medicine. 352(17):1741-1744. April 28, 2005.

6. ^ Baker MD. Major trauma in children.Rudolph's Pediatrics, 21st Ed. McGraw-

Hill. 2003.7. ^ Berg J. Tymoczko, JL; Stryer, L.Biochemistry. 5th Ed. WF Freeman & Co.

2001. (Hosted on the web by the National Library of Medicine.)

8. ^ Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia

of inflammation.Blood102(3): 783-788. 1 Aug 2003.9. ^ Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. J Clin

Invest 113(9):1251-3. May 2004.
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