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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
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