Iron Unit Flashcards
Is iron essential? What happens if it is not in the right amounts?
- One of the most abundant compounds on earth
- Iron is a cofactor for many cell functions, but also a catalyst of free radical reaction (Can cause oxidative damage)
- Scarcity and excess have important consequences and epidemiological significance
- Iron homeostasis and balance are tightly regulated
Is Iron deficiency common?
- Iron deficiency is the primary nutritional disorder in the world (affects 2 billion people)
- Iron deficiency is so important it can impact the GDP of nations (impacts wellness and productivity)
What is hereditary hemochromatosis?
- Iron overload caused by a genetic disorder
- Can cause increased iron deposits in cell which catalyzes free radical reactions
Is the body able to store iron?
- Yes can absorb extra iron and store it when we need it
- Potentially adapted this over time
- Hepsidin amounts changed over time, when high levels would decrease iron absorption and when low would have increased iron absorption
Iron is considered a ____________
Micromineral
What are the oxidation states of iron? What does this mean
- Most common forms are ferrous: 2+ and ferric= 3+
- This means iron is a transition element, meaning it forms one or more stable ions
- Oxidative states of iron allow for transfiguration changes of protein
Iron complexes result in…
Stable geometry in a molecule or cluster (analogous to Lego or scaffolding; linking proteins together)
What is iron required for?
- Required for the synthesis and activity of many proteins; hundred of biological reactions depend on iron
- Major component of hemoglobin (carries oxygen to all parts of the body) which is the largest source of iron in the body
- Critical role in cells assisting in oxygen utilization, enzymatic systems (especially for neural development), and overall cell function
- Essential for brain development
What is heme?
- Most well-known iron-containing protein and contains heme; carries O2 throughout the body
- e.g. O2 carriers (hemoglobin, myoglobin), e-transfer/transport (cytochrome of ETC), activation of O2 or peroxides (cytochrome P450, nitric oxide synthase, catalase, some peroxidases)
What does cytochrome P450 do?
- Important in the metabolism of LCFA and toxic chemicals. Converts to less toxic form
- Heme containing enzyme
- Cytochrome P450 enzymes - first line of defense against toxins - central involvement in metabolism of steroids, drugs and chemical carcinogens
- Iron atom in heme group takes electrons, uses to charge an oxygen atom (making it highly reactive)→ oxygen atom can make many changes on different toxic molecules
- Examples of molecules oxidized by cytochrome P450: caffeine, acetaminophen, nicotine, diazepam, aniline and benzene
What is non-heme?
- Iron-containing protein that does not have heme
- Important in oxygen transport and metabolism
- E.g. Fe-S clusters (e-transfer proteins NADH dehydrogenase, cytochrome c reductase), single Fe atoms, oxygen bridged Fe
- Found in plant sources
Why are dark leafy green vegetables a good source of iron?
- Iron important in photosynthesis so that is why it is in vegetables
Explain the structure of heme and hemoglobin
- Hemoglobin contains 4 heme groups, 2 alpha subunits, and 2 beta subunits. Each subunit has a heme group
- Each heme group contains an iron
- So hbg contains 4 Fes
How many oxygen molecules does Hb transport and how is this involved in respiration?
- One Hgb transports up to 4 Oxygen molecules (RBC approx 280million Hgb)
- In lungs Ox binds to oxyhemoglobin → transports via blood to tissues →Oxygen released to myoglobin → transports to mitochondria →aerobic respiration → deoxyhemoglobin picks up 2H+ + 2CO2 → returns to lungs → CO2 released
How is iron involved in the electron transport chain?
- Both heme and non-heme iron-containing enzymes function as electron carriers (one electron transfer involved in Fe2+/Fe3+ oxidation states)
- These include cytochrome (most have heme prosthetic groups), i.e. Cytochrome B contains the same iron porphyrin as hemoglobin and myoglobin AKA cytochromes contain iron
- Non-heme proteins include the iron-sulfur (Fe-S) proteins
Name 2 other important roles of iron?
1)Protein with oxygen-bridged iron (stability)
- i.e. Ribonucleotide reductase (converts ribonucleotides to deoxyribonucleotides) →essential for DNA transcription
2) Single-Fe containing metalloenzymes
- i.e. alpha-ketoglutarate (CAC) - critical with Vitamin C for post-translational modification of pro-collagen (pro-collagen must be modified before secreted)
- i.e. Dioxygenases such as 5-lipoxygenase (eicosanoid synthesis) and cysteine dioxygenase (cysteine catabolism and taurine synthesis)
How much iron do we lose per day and how does this occur?
- Basal Iron loss per day is from GIT, skin, epithelial lining (urinary) sloughing where we lose our iron stores
- = 1.0mg for 70kg M, =0.75mg for 55kg female (smaller) but menstruation can double loss = 1.5mg (also increases in parturition due to blood loss, lactation due to formation of breast milk)
- Greatest need for iron is during periods of growth or blood loss because we store so much iron in Hgb
Based on how much we lose per day, how much iron do males and females need to absorb?
- Males need to absorb approx 1mg
- Females >1.5mg
- Late stage pregnancy 4-5mg to maintain blood volume in the fetus
How much iron do infants need? Why do they need this amount?
- AI for infants 0-6 mos is based on mean intake of healthy breastfed infants
- 0.27mg AI, UL = 40mg
- High needs due to rapid growth, but high bioavailability + sufficient iron stores for ~4-6mos, thereafter many weaning foods are iron-fortified
- Breastmilk doesn’t have much iron but in the form of lactoferrin which is more bioavailable
Why are weaning foods iron-fortified?
Infants have good iron stores when they are born at term. As they get older (4-6mos) they start to run out of stores as there are low amounts in breastmilk. This is why weaning foods like cereals are fortified
What are EARs of iron based on?
- Based on factorial modeling using basal iron losses, menstrual losses, fetal requirements in pregnancy, growth and expansion of blood volume, increased tissue and storage iron
What are the DRIs for iron of people in different life stages?
Why are RDAs higher than EAR?
- EAR meet the needs of half of the population whereas RDA meets the population of 97%. Needs to be much higher because there is a high variability of iron losses
Why are the DRIs for non-vegetarians higher? How much higher?
- Vegetarians 1.8x higher
- Not eating meat so getting non-heme which has lower bioavailability
- Consuming inhibitors of iron as well
Why is the RDA for women taking oral contraceptives lower than non?
- 10.9mg vs 18mg because they do not have menstrual losses
What is the UL of iron and why is that set?
- 40mg and 45mg. Iron is toxic in high quantities
- Too much supplementation can decrease absorption
- Would want to take supplements every other day
What are good food sources of iron?
- Meat and meet substitutes are high in iron such as clams, oysters, liver, beef chuck (dark meat cuts)
- Legumes particularly soybeans are high (important to look at serving size)
- Fortified cereals
- Vegetables and fruits
Where can you find heme iron vs non-heme iron in foods?
- Heme iron sources: 50-60% of iron in animal products, e.g. meat, fish, poultry (in hemoglobin and myoglobin)
- Animal sources also contain non-heme iron
- Non-heme iron sources: plant foods (e.g. nuts, fruits, vegetables, grains, tofu), dairy products (e.g. milk, cheese, eggs - have low amounts)
- Heme accounts for about 10% of the average daily iron intake, but it is well absorbed (about 25%). Nonheme iron accounts for the remaining 90% but it is less well absorbed (about 17%)
How is heme iron absorbed and how much is absorbed?
- Heme iron: animal meat/muscle: red meat, poultry, fish (~25% absorbed)
- Hydrolyzed from hemoglobin/myoglobin in stomach and small intestine (…HCl proteases)
- Heme absorbed intact by heme carrier protein (Hcp 1)
- Hydrolyzed to inorganic ferrous Fe and protoporphyrin (i.e. iron separated)
- NB: little regulation of HEME IRON, relatively consistent
How is non-heme iron absorbed and how much is absorbed?
- Animal and plant-derived (<17% absorbed)
- Hydrolyzed from food components in stomach → mostly Fe3+ released into SI (may complex to ferric hydroxide Fe(OH)3 - relatively insoluble), some Fe2+ (fairly soluble) → Fe2+ absorbed via divalent metal (cation) transporter 1 (DMT1)
What increases and decreases Ferric absorption?
- Fe3+ absorption increased by acidic environment as it can cause conversion of ferric into ferrous which improves absorption
- Chelation of Fe improves absorption
- Zn, Mn, Cu, Ni, Lead transported by DMT1. If many of those molecules present they compete with iron for absorption
Why do kids have increased risk of lead toxicity?
- DMT1 transporter systems are increased during deficiency in children so when lead is present it can lead to more absorption of lead into the system
Explain the steps of iron digestion, absorption, enterocyte use, and transport
1) Iron is released from bound food components. Some HCl in the stomach may reduce Fe3+ to Fe2+
2) Free heme is absorbed intact by heme carrier protein (hcp) 1, located primarily in the proximal small intestine.
3) Within the enterocyte, heme is catabolized by heme oxygenase to protoporphyrin and Fe2+
4) Nonheme iron in the small intestine may react with one or more inhibitors, which promote the fecal excretion of iron
5) Any of the three reductases, cytochrome b reductase 1, cytochrome b (558) ferric cupric reductase, and six trans-membrane epithelial antigen of the prostate (step) 2, may reduce Fe3+ to Fe2+
6) Divalent metal transporter (DMT) 1 carries Fe2+ across the brush border membrane into the cytosol of the enterocyte, although endocytosis of DMT1 as part of transcytosis ay also enable iron absorption
7) Fe2+ may bind to poly rC binding protein or a yet unidentified protein for transport in the cytosol; iron may also be used within the cell or stored as part of ferritin
8) Ferroportin transports iron across the basolateral membrane. Iron transport is coupled with its oxidation to Fe3+ by hephaestin
9) Fe3+ attaches to transferrin for transport in the blood
What is chelation?
The claw-like way in which a mineral is bound to an organic molecule. E.g. Ferrous is chelated to cytosolic proteins when in the cell
Iron balance is primarily determined by ______________
Iron absorption
Give examples of increased need for absorption. What is this a result of?
- Increased need for iron = Increased absorption
- Occurs in iron deficiency, pregnancy, hypoxia (need more Hb), erythropoiesis (making of RBC)
- These factors are due to increased expression of:
- DCYTB - brush border membrane = reductase. (ferric into ferrous)
- DMT1 = transports it into the cell
- Ferroportin = transports from cell into blood stream
What occurs when body stores of iron are high?
- Expression of brush border transporters decrease, liver secretes hepcidin which binds ferroportin, targeting it for degradation so iron can’t go into blood. enterocyte iron is lost in feces
- Iron stored as ferritin is lost in 3 days through sloughing
- Genetic regulation = brush border transporters
- Hormonal regulation = hepcidin secreted from liver
What will occur if someone has low iron?
- Use ferritin storage
- Ferroportin upregulated
- Increased proteins to get iron in as well
If we had 15mg/day of iron in our diet how much would get into our body? I.e. Phases of iron absorption
- 15mg = iron in diet
- 7.5mg is the amount of iron available in Ferrous (fe2+) form and solubilized
- 4.0mg of that is taken up by mucosal cells into ferritin
- 1.5-2.0mg is the final amount released into plasma for re-uptake by transferrin ( ferrous to ferric oxidized by hephaestin)
What factors can increase iron absorption?
- Meat factor protein (MFP) if consumed in the same meal can increase non-heme(AAs? Unclear)
- Vitamin C is acidic, solubilized Ferric to ferrous (May be a weak chelator of iron)
- Some acids/sugars: i.e. ascorbic acid, citric, lactic, gastric, and tartaric acid facilitate absorption of non-heme iron
What factors can decrease iron absorption?
-The following factors can compete or interfere with the binding process:
- Phytates, polyphenols, fibres, soy (fermented soy i.e. miso and soy sauce), whole grains, nuts
- Some acids: Oxalates/Oxalic acid (spinach, beets, rhubarb), tannic acid (tea, coffee)
- Some minerals/salts: Calcium, calcium phosphate salts, zinc, manganese, nickel (Compete for absorption, and transport, negative charge bind cations. Weak chelators help protect from strong/tight but strong chelators no longer absorbable )
- EDTA (Antioxidant - chelates with metals and reduces ability to oxidize the food)
What can occur in a vegan diet?
- Estimated only 10% absorbed
- Non-heme iron + increased intake of oxalates, phytates + no MFP
- Conversely a ‘mixed’ diet ~20% absorbed
Explain how intraluminal factors can impact iron absorption
- Any condition or situation that reduces protein digestion and/or nutrient absorption:
- Rapid transit time (e.g. eating lactose with a meal if you are lactose intolerant)
- Malabsorption syndromes
- Lack of digestive juices or gastric acidity, excessive use of antacids (take between meals so it does not limit absorption of nutrients)
Can iron absorption be upregulated?
- Yes it can be but in situations where you absorb iron that isn’t bioavailable (e.g. vegan) it doesn’t matter how much upregulation occurs you still won’t be able to absorb it
What are the absorption amounts of different iron forms?
- Some irons are more bioavailable than others. Succinate, lactate, fumarate most absorbable
- Food/supplements fortified with different types/chelated with iron. It is important to see what these types are in order to know how much iron you are absorbing
- If iron is already chelated in ferrous form, will the intake of organic acids increase bioavailability?
- Ferrous salts more absorbable than ferric salts
What are the main causes of iron deficiency?
- Generally due to blood loss
- Poor diet and/or reduced iron absorption may contribute to decreased iron in diet, or decreased iron utilization (i.e. copper or vit A deficiency)
What is the approximate iron distribution in male and female adults? (mg Iron/kg body weight)
- Functional iron ~78% - Mainly hemoglobin 2/3 of total iron in the body
- Transport Iron ~0.001% - Transferrin
- Storage Iron ~22% - Ferritin + hemosiderin
- Males have larger proportion of FFM so have greater amounts of iron (50.05 vs 39.05)
Explain the process of iron recycling
- Transport Iron amounts are coming from the gut, ferritin, and myoglobin with myoglobin being the most and ferritin being second
- These storage amounts and dietary amounts = 24mg
- Of that 24mg some is used for heme synthesis in marrow which is required for erythropoeisis
- 17mg of that iron is carried via Heme
- 15mg is recycled and stored as ferritin and hemosiderin. Recycling side breaks down heme to provide iron back into blood stream
- 22mg recycled back to beginning where dietary amounts, etc. come in
How does ferritin work? Average store?
- Fe2+ (movement form) enters via channels → to Fe3+ (storage form) in H subunits → Migrates to interior L subunit
- Subunit proportions vary by tissue - storage vs. detoxification (I.e. L rich types in liver and spleen, H-rich found in heart and brain)
- Average store/apoferritin = 1200 iron atoms (max = 4500)
- Diagram: ~30% L-type (storage) and 70% H-type (detox) subunit; similar ratio in the brain
For iron deficiency, chronic disease/inflammation, and mixed deficiency (B12, folic acid, iron) what would hepcidin levels , transferrin saturation, ferritin, and soluble transferrin receptors be at?
What are indicators of depleted iron stores, early functional iron deficiency, and iron deficiency anemia?
How will marrow iron stores, transferring iron binding capacity, plasma ferritin, plasma iron, transferrin saturation, RBC protoporphyrin and erythrocytes change with:
1. Iron overload
2. Increased iron stores
3. Normal
4. Reduced iron stores
5. Iron depletion
6. Iron deficient erythro-poeisis
7. Iron deficiency anemia
What is the function of hepcidin?
- Hepcidin acts to degrade ferroportin
- It is the major regulator of iron metabolism
- When activated it degrades ferroportin so iron is not transferred to other areas of the body and it stays within the cell (then can be sloughed off)
Explain the transferrin cycle
- Transferrin binds Fe3 with high affinity
- Tf-Fe3 binds to transferrin receptor on cell surface
- Internalized by receptor-mediated endocytosis
- Endosome becomes acidic and Fe3 released
- Fe3 converted into Fe2 by STEAP3
- Transported out of endosome by DMT1
- Fe2 stored as ferritin or hemoglobin
- TfR complex released out of cell
