Iron Flashcards
(120 cards)
1
Q
What is the essentially of iron vs. The toxicity of iron?
A
Iron is an essential cofactor but can be toxic and promote free radical oxidation
2
Q
What is the prevalence of iron deficiency?
A
Primary nutritional deficiency in the world ~1-2 billion people
- Can effect GDP of nation
- developing: 50% children & pregnant women
- western: ~10% females
3
Q
What is the prevalence of hemochromatosis?
A
Iron overload which is one of the most common genetic disorders
4
Q
How has evolution influenced iron absorption?
A
Varies due to evolutionary pressures
- When deficient the boy improves absorption and vicversa
5
Q
What classification is iron?
A
Micromineral
6
Q
What is the most relevant oxidation states of iron in terms of nutrition?
A
- Ferrous: Fe2+
- Ferric: Fe3+ (oxidized form)
7
Q
Why is iron important for enzyme and protein function?
A
- forms a stable geometry in protein
- Required for synthesis and activity of many proteins
- Required for many biological reactions
8
Q
What are the forms of iron that come from food?
A
- Heme: 50-60% of iron in animals products
- non-heme: sources from plants, animals, dairy products
9
Q
What are some examples of heme proteins that require iron?
A
- hemogobin and myoglobin: O2 carriers
- cytochromes of ETC: 1 e-transfer/transport
- cytochrome P450: detoxification
- others: nitric oxide synthase, catalases, some peroxidases - invovled in activation of O2 or peroxides
10
Q
What are some examples of non-heme proteins that require iron?
A
- Fe-S clusters in NADH dehydrogenase and cytochrome c reductase: 1 e-transfer proteins
- single Fe atoms
- oxygen bridged Fe: provides stability
11
Q
Describe the heme in hemoglobin
A
hemoglobin is made up of 4 protein subunits which are covalently bonded to a heme group containing iron.
* transport 4 O2
12
Q
How many hemoglobins are in 1 RBC?
A
~280 million
13
Q
What are the general steps of O2 in and CO2 out?
A
- In lungs O2 binds to oxyhemoglobin
- transported via blood to tissues
- O2 is released to myoglobin
- transported to mitochondria
- aerobic respiration occurs
- deoxyhemoglobin picks up 2 H+ + 2 CO2
- returns to lungs
- CO2 is released
14
Q
What is heme without the iron?
A
porphyrin ring
15
Q
What proteins in the ETC have heme and non-heme proteins?
A
- heme: cytochromes
- non-heme: iron-sulfur proteins
both are only 1 electron carriers
16
Q
What is the role of cytochrome P450?
A
- first line of defense against toxins
- central involvement in metabolism of steroids, drugs and chemical carcinogens
- the heme iron takes e- and uses it to charge an O2 making it highly reactive such that it can make changes to the molecules
17
Q
What are examples of molecules that can be oxidized by cytochrome P450?
A
- caffeine
- acetaminophen
- nicotine
- diazepam
- aniline
- benzene
18
Q
What is an example of a protein with oxygen-bridged iron?
A
ribonucleotide reductase
* converts ribonucleotides to deoxyribonucleotides which is important for DNA transcription
19
Q
What is an example of a protein containing single-Fe?
A
- α-ketoglutarate in the citric acid cycle
- the dioxygenase 5-lipoxygenase for eicosanoid synthesis
- the dioxygenase cysteine dioxygenase for cysteine catabolism & taurine synthesis
20
Q
When is the greatest need for iron?
A
periods of growth and blood loss
21
Q
What is the basal iron loss per day?
A
GIT, skin, epithelial lining sluffing off (urinary)
* 70 kg male: 1.0 mg
* 55 kg female: 0.75 mg
* menstruation: 1.5 mg
* increased also in pregnancy, parturation, lactation
22
Q
How much iron needs to be absorbed by males and females per day?
A
- males: ~1 mg
- females: >1.5 mg
- late stage pregnancy: 4-5 mg
23
Q
How do infants get iron?
A
- 0-6 months: Based on AI from breastmilk which does not have much but it is highly bioavailable form called lactoferrin and they have sufficient stores for ~4-6 months
- 7-12 months: weaning foods are iron fortified as they start to lose stores
24
Q
How are the EARS for iron determined?
A
factoral modelling taking into account:
* basal irons losses
* menstrual losses
* fetal requirements in pregnancy
* growth and expansion of blood volume
* increases tissue & storage iron
25
What are the iron DRIs?
Based on RDA:
* males 19-50: 8 mg/day
* females 19-50: 18 mg/day
26
What is the difference between the EAR and the RDA DRIs?
* EAR: closest to needs of most people
* RDA: needs to meet 97% of population
27
How much more iron do vegetarians need?
1.8x more
* bioavailability of non-heme from plants is lower and usually has inhibitors
28
What is the RDA for women taking oral contraceptives?
10.9 mg
* lower because the contraceptive tends to reduce mentstrual losses
29
What is the reccomendation of supplements for those with defficiency?
recommendation now is to take a moderate ~35mg every other day instead of a high dose everyday
* DRIs are for healthy individuals. If you have an actual deficiency the supplement will probably be pretty high. To high or too often though may suppress absorption of iron.
30
Common food sources of iron
31
What food source has really high iron?
3 oz clams: 12-24 mg
32
What makes heme iron more bioavailable for absorption than non-heme iron?
the intestine can only absorb the Fe2+ state of iron which is what is contained in heme, therefore heme can be absorbed intact into the enterocyte where iron can than be extracted. Non-heme iron is the Fe3+ state so it must first be reduced in the intestine to Fe2+ before it can be absorbed into the enterocyte.
33
What is the bioavailability difference between heme iron and non-heme iron?
* heme: ~25% absorbed
* non-heme: <17% absorbed
34
Describe the absorption process of heme iron
1. HCl and proteases release the globin and the heme for myglobin and hemoglobin in the GI
2. Free heme is absorbed intact by heme carrier protein (hcp1), found primarily on proximal SI
3. In the enterocyte, heme is catabolized by heme oxygenase to protoporphyrin and Fe2+
7. Fe2+ binds to cytosolic proteins via rC binding protein and which can then go to functional use within the cell OR stored as part of ferritin OR absorption
8. ferroportin transports iron across basolateral membrane by coupling transport with the oxidation of Fe2+ to Fe3+ by hephaestin
9. Apotransferrin has a high affinity for Fe3+ picking it for transfer as transferrin-Fe3+
35
Describe the absorption process of non-heme iron
7. non-heme iron is released from the protein where some HCl make reduce Fe3+ to Fe2+
8. The iron may react with inhibitors and be excreted
9. A reductase reduces Fe3+ to Fe2+
10. Fe2+ carried into enterocyte via divalent metal transporter (DMT1)
8. Fe2+ either transported to cytosolic proteins via rC binding protein OR functional use within the cell OR stored as part of ferritin
8. ferroportin transports iron across basolateral membrane by coupling transport with the oxidation of Fe2+ to Fe3+ by hephaestin
9. Apotransferrin has a high affinity for Fe3+ picking it for transfer as transferrin-Fe3+
36
What are some inhibitors of iron absorption?
* alkaline pH
* polyphenols
* oxalic acid
* phytic acid
* phosvitin
* divalent cations
37
How is iron balance determined?
primarily by iron absorption
38
When does absorption of iron increase?
When there is an increased need
* iron deficiency
* pregnancy
* hypoxia
* erythropoesis
39
How does iron absorption increase?
An increased duodenal expression of:
* brush border reductases to convert ferric to ferrous
* DMT1 to transport more into enterocyte
* ferroportin to transport more into circulation
40
What happens the enzymes and transporters of iron absorption when stores are high?
* expression of the brush border transporters decreases
* the liver secrete hepcidin which targets and binds to ferroportin for degradation and is sluffed off and exctreted with the 3 day turnover of enterocytes
41
What are the relative quantities of iron involved in the phases of iron absorption?
1. **iron solubilized**: only about half is solublized and available in ferrous form
2. **Iron uptake by mucosa**: only about half of what is solublized is actually taken up be enterocytes
3. **Iron absorbed**: only about half of that is then released to circulation
42
What factors increase iron absorption (enhancers)?
* meat factor protein (MFP) consumed in same meal for non-heme
* Acidity of vitamin C can solubilise 2+ to 3+
* Other acids and sugars: citric, lactic, gastric
43
What factors decrease iron absorption (inhibitors)?
* phytates, polyphenols, fibre, soy, whole grains, nuts
* oxalates/oxalic acid in spinach, beets, rhubarb
* tannic acid in tea and coffee
* some minerals/ salts: Ca, Zn, Mn, Ni
* EDTA
44
How do inhibitors effect iron absorption?
* large molecules can physically block
* act as strong chelators, tightly binding the iron and interfering with absorption
* divalent metal transporters are not specific so other elements may compete
45
What is the effect of a vegan diet on reduced iron absorption?
only about 10% absorbed because it is only non-heme iron which usually means more oxalates and phytates and no MPF so lots of inhibitors. Even if the system is upregulated for iron absorption, the body will not take in what is not bioavailable
46
What are some intraluminal factors that can decrease iron absorption?
Any condition or situation that reduces protein digestion &/or nutrient absorption
* Rapid transit time such as fibre
* Malabsorption syndromes
* Lack of digestive juices or gastric acidity, excessive use of antacids
47
What is the reccomendation for antacids?
Usually reccomended take between meals or before bed to prevent it from effecting iron absorption
48
Relative absorption of different iron forms
49
What are chelators?
molecules that bind metal ions
* small molecules (EDTA, AAs)
* complex proteins (mucin, albumin, transferrin)
50
What happens with free iron if not chelated?
Can precipitate and collect in cells
* toxic effect can happen within seconds
51
What is the major purpose of iron chelation?
iron homeostasis
* Binds to, solubilizes & makes iron unavailable for things such as ox reactions, toxicity, bacterial growth
52
What are chelators in intestine that increase iron absorption?
weak chelators: ascorbate & citrate
* help solubilize iron with loose binding and transfer it from compounds to mucosal cells
53
What are chelators in intestine that decrease iron absorption?
strong chelators: plant phytates, tannins, Ca
* prevent uptake and absorption
* can act as antioxidants if absorbed unbound
54
Use of chelation therapy for iron excess and overload
putting chelators into circulation bind to iron, neutralizing it and can then be easily extreted protecting cells from iron mediated toxicity. iron-chelating agents bind iron specifically and can be excreted whereas other chelators are broad-spectrum.
* patients with anemia + iron overload
55
What are some iron-chelating agents that can be used for iron excess?
* desferroxamine
* deferasirox
56
What are reccomendations to maximize iron intake?
* Iron-enriched foods
* co-nutrient feeding
* use iron cookware
* supplements
57
What are specific reccomendation around taking iron supplements?
* Recommended in pregnancy, infants, children
* Ferrous sulfate or iron chelate preferred
* Take between meals (not with milk, tea/coffee)
* Juice does not aid supplemental Fe absorption
58
How does turnover influence iron availability?
Hemoglobin, ferritin & hemosider in degradation yield plasma iron via recycling
59
How does excretion influence iron availability?
* Mostly GI tract (blood, bile, desquamated mucosal cells)
* skin (desquamation of surface cells)
* urine
* larger losses with hemorrhage, menses
60
What is the approximate iron distribution in adults?
* ~78% functional iron, mostly Hgb (2/3 of total iron in body)
* ~0.001% transport iron, transferrin
* ~22% storage iron, ferritin
men more distribution than women (typically larger portion FFM)
61
How much iron do we need for body function in a day?
~20 mg/d
* diet: 1-2 mg
* reutilization/ recycled: 18 mg
62
Approximately how much iron is stored?
28-32 mg/kg
* females: 1540 mg
* males: 2240 mg
63
How is iron recycled?
turnover of senescent RBCs every ~ 120 days via mononuclear phagocytic system cells (macrophages) which break down heme, releasing to be reused by cells.
64
What are the iron transport & storage proteins?
* Transferrin (Fe3+)
* Lactoferrin (Fe3+)
* Divalent metal transporter 1(DMT1) (Fe2+)
* Ferroportion (Fe2+)
* Ferritins ( Fe3+)
* Hemosiderin (Fe3+)
65
Describe role of transferrin
Transports iron (Fe3+) in the circulation, supplies iron to cells
66
Describe role of Lactoferrin
Binds and removes iron from the circulation in infection and is bioavailable form of iron for infants in breasmilk
67
Describe role of DMT1
* Transports Fe2+ across the apical membrane of enterocytes of the duodenum
* transports Fe2+ released from the transferrin–transferrin receptor complex, after its reduction by STEAP out of endosomes
in both cases this symporter also transports H+
68
Describe role of ferroportin
* Exports Fe2+ across the basolateral membrane of duodenal enterocytes
* exports Fe2+ from macrophages and hepatocytes
* acts with the multicopper oxidases
ceruloplasmin and hephaestin to load apotransferrin with Fe3+
69
Describe role of ferritins
Stores iron (Fe3+) in the cytosol of many cells
* synthesis is subject to regulation by iron regulatory protein/iron-responsive element
70
Describe role of hemosiderin
Stores iron (Fe3+) within lysosomes in conditions of iron loading
71
What are the transferrin-binding proteins?
* transferrin receptor 1 (TfR)
* transferrin receptor 2
72
Describe role of tfR
Principal protein for transferrin iron uptake, subject to regulation by iron regulatory proteins/iron-responsive elements
73
Describe role of transferrin receptor 2
Important for sensing iron levels
* Secondary protein for transferrin iron uptake, not subject to regulation by iron regulatory proteins/iron-responsive elements; involved in regulation of hepcidin transcription
74
Proteins of iron recycling to know
* ceruloplasmin
* hephaestin
* duodenal cytochrome b (DcytB)
* STEAP (six transmembrane epithelial antigen of the prostate)
75
Describe role of ceruloplasmin
Circulating multicopper oxidase that oxidizes Fe2+ to Fe3+ from cells ubiquitiously before its incorporation into apotransferrin
76
Describe role of hephaestin
Multicopper oxidase that oxidizes Fe2+ to Fe3+ before its incorporation into apotransferrin at the the enterocyte into circulation
77
Describe role of DcytB
Metalloreductase that reduces Fe3+ to Fe2+ before transport by DMT1 at the apical membrane of duodenal enterocytes
78
Describe role of STEAP
Metalloreductase localized within endosomes that reduces Fe3+ to Fe2+ before transport by DMT1 into cells ubiquitously throughout the body
79
Role of iron in erythropoiesis
Heme in RBCs is formed when transferrin-bound iron is taken up by erythroblast in marrow & complexed in protoporphyrin in mitochondria
* Requires ~24 mg Fe (~17 mg incorporated into Hgb) daily + constant supply of vitamin B12 & folic acid for production of RBCs in the marrow.
* Iron regulates globin synthesis at transcriptional and translational levels, availability is regulated to ensure adequate supply for Hgb
80
What stimulate erythropoesis
Hypoxia detected in the kidney, releases erythropoeitin, stimulates erythropoiesis
81
How RBCs are produced/ recycled each day?
Every day ~30 trillion RBCs are produced & approximately the same amount recycled via breakdown of senescent RBCs
82
How does high RBC turnover effect iron status?
may take 2-6 weeks to ↑Hgb with ↑iron intake and a long time for Hgb to deplete if iron intake is inadequate
83
General process of mononuclear phagocytic system
1. Lysed in lysosomes of macrophages
2. heme is broken down & iron exported into cytosol
3. exported from macrophages via ferroportin into plasma and reduced by ceruloplasmin
4. loaded onto transferrin
84
What is the major transport protein in plasma?
transferrin
* apotransferrin: protein with no bound cations (high binding affinity)
* monoferric transferrin: protein bound to iron
* diferric transferrin: protein bound to 2 irons (fully saturated)
85
Where is apotransferrin synthesized?
The liver
86
What ensures limited toxicity/free radicals of iron?
The presence of apotransferrin and ceruloplasmin in plasma has high affinity for Fe3+ so they immediately chelate and preventing toxicity
87
What is the saturation of transferrin with iron?
~30%
Transferrin saturation is a total of all the transferrin mixes! The apo quickly picks ups whatever is around and then the diferric delivers immediately to cells since cell receptors have a high affinity for diferric. Total saturation is mostly apo and monoferric hence normal saturation is about this.
88
How much iron can Tf carry?
2 lobes so 2 Fe3+
89
How is transferrin saturation calculated?
TSAT = [serum iron] / TIBC x 100
* example: If normal [transferrin] in plasma = 2.5 g/L or 30 mmol/L, and each Tf has 2 binding sites, then total potential binding = 60 mmol/L iron = Total iron binding capacity (TIBC)... so if serum [iron] is 20 mmol/L then Tf would be ~1/3 saturated and TSAT would be 30%
90
What is considered low and high TSAT?
* <30% indicates depleted iron stores
* <15% iron deficient erythropoeisis
* >60% dangerous excess
91
What happens in early deficiency through continued iron depletion?
1. **Ferritiin picks up the slack**: early on serum Tf increases but iron stores not yet depleted so serum [Fe] is normal = low to normal % saturation + high TIBC
2. **Ferritin cannot pick up slack anymore**: when stores depleted, serum Tf still elevated but serum [Fe] low = low % saturation + very high TIBC
92
What is ferritin important for?
safe storage of iron: soluble, non-toxic, bioavailable form
93
What are the major sites of ferritin?
* spleen: reticulo-endothelial system
* liver and skeletal muscles: parenchymal cells
* serum: reflects iron stores
* muscle and heart: particularly sensitive to oxidative damage
94
What is normal range for ferritin?
18-270 (M) or 18-160 (F) ng/mL or mcg/L
* low: iron depletion (low serum iron + low ferritin)
* high: iron overload or inflammation (acute phase protein)
95
Describe the structure of apoferritin and how it works?
ferritin without iron that has 24 sub-units either L or H
* Fe2+ enters apoferritin via channels and is oxidazed to Fe3+ in H subunits than migrates to interior L subunits
96
How do the L and H subunits of apoferritin differ?
Subunit proportions vary by tissue - storage vs. detoxification
* storage: L-rich, liver and spleen
* detoxification: H-rich, heart and brain (70% H; 30% L in brain)
97
What is hepcidin?
Protein that degrades ferroportin through internalization via binding to prevent absorption of iron overload
98
When is hepcidin reduced and induced?
* **reduced**: need for increase in iron demand
* **induced**: iron loading to reduce absorption
99
What factors regulate inducing hepcidin?
* inflammation
* iron
* bone morphogenic protein signalling
100
What factors regulate reducing hepcidin?
* erythropoietic demand
* hypoxia
* eodcrine regulation
101
Where is ferroportin predominantly expressed?
* macrophages
* duodenum
* hepatocytes
102
What is the average store of Fe/ apoferritin?
1200 iron atoms
103
Describe the TfR
Transferrin Receptor
Trans-membrane glycoprotein important for cellular uptake of iron via receptor mediated endocytosis.
* extracellular domain = binding site
* cytoplasmic domain = intracellular trafficking/ signal for endocytosis
104
What are the two types of TfR?
* TfR1: more involved in uptake
* TfR2: more concerned with sensing iron
105
What happens to apotransferrin and the TfR once iron load has been depositied in the cell?
apotransferrin will return to circulation (~3-10 min) along with pieces of the transferrin receptor ends called soluble transferrin receptor (sTfR)
106
Describe the transferrin cycle for iron uptake
1. apoTf binds Fe3+ with high affinity to form Tf at neutral pH
2. Tf-Fe binds to the TfR and is internalized via receptor-mediated endocytosis forming an endosome
3. With decreased pH, Fe3+ is released from the Tf-TfR-Fe and then converted Fe2+ by STEAP3
4. The Fe2+ leaves the endosome via DMT1
5. Fe2+ can be stored in ferritin in non-erithroid cells or incorporated into Hb in erythroid cells.
6. The apoTf-TfR complex is recycled back out via excocytosis.
107
Describe the sTfR
soluble transferrin receptor
This is a piece of the extracellular domain of the tissue TfR that is cleaved in the cell and released into plasma which circulates as transferrin + receptor complex
* TfR will be recycled back to the membrane a few times before being sluffed off into circulation as sTfR
108
What is the largest contributor to sTfR?
erythroblasts (depends on marrow erythropoietic activity)
109
What do sTfR levels indicate?
The bodies need for more iron
* ↑ erythropoetic acitvity = ↑ sTfR
* Iron status: ↑sTfR if deficient (↑TfR expression)
110
-What are IREs?
iron responsive elements
Are part of mRNA for many proteins and activation of a single protein via binding proteins (IRE-BPs) has different effects on ferritin and transferrin receptor synthesis
111
What is the effect if low and high iron on IRE?
* ↓Fe: activates BPs which decreases ferritin production (blocks formation of ferritin mRNA polysomes) and increases TfR synthesis (stabilizes TfR mRNA)
* ↑Fe: inactivates BPs so ferritin synthesis proceeds
112
assessment for:
* plasma ferritin
* transferrin saturation
* Hb
* plasma transferrin receptor
* total body ferritin iron
* iron absorption
113
What are normal levels for Hb plasma ferritin?
* Hb females: 120-160 g/L
* Hb males: 135-175 g/L
* serum ferritin: 100±60 ug/L
114
What are the stages of iron depletion?
1. iron storage depletion
2. mild iron deficiency without anemia
3. iron-deficiency anemia
115
What are the serum levels of these iron measures for types of anemia (low, normal, high)?
116
What are functional indicators of iron deficiency?
* impaired work capacity
* impaired cognitive function
* Delayed psychomotor development (infants)
* Delayed immune function & intellectual development (children)
* Pregnancy complications (premature delivery, low birth weight, maternal anemia, increased perinatal infant mortality)
* lead toxicity
117
Main causes of iron deficiency?
Generally due to blood loss, poor diet &/or reduced iron absorption
* diet: May contribute to ↓iron in diet, or ↓iron utilization
118
Who is most at risk for iron deficiency?
* infants, especially premature
* children
* teens
* women of childbearing age
* kidney dialysis
* GIT issues
* exclusionary diets
* internal bleeding
119
Describe hemochromatosis
Iron toxicity & overload
Body absorbs 2 to 3x normal amount of iron and accumulate ~0.5 to 1 g/y due to mutation in HFE gene so cannot accuratelt sense iron stores so hepcidin is not released
* transferrin becomes highly saturated and ↑ free radical formation
120
symptoms of hemochromatosis
