Iron Unit Flashcards
(114 cards)
1
Q
Is iron essential? What happens if it is not in the right amounts?
A
- 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
2
Q
Is Iron deficiency common?
A
- 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)
3
Q
What is hereditary hemochromatosis?
A
- Iron overload caused by a genetic disorder
- Can cause increased iron deposits in cell which catalyzes free radical reactions
4
Q
Is the body able to store iron?
A
- 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
5
Q
Iron is considered a ____________
A
Micromineral
6
Q
What are the oxidation states of iron? What does this mean
A
- 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
7
Q
Iron complexes result in…
A
Stable geometry in a molecule or cluster (analogous to Lego or scaffolding; linking proteins together)
8
Q
What is iron required for?
A
- 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
9
Q
What is heme?
A
- 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)
10
Q
What does cytochrome P450 do?
A
- 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
11
Q
What is non-heme?
A
- 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
12
Q
Why are dark leafy green vegetables a good source of iron?
A
- Iron important in photosynthesis so that is why it is in vegetables
13
Q
Explain the structure of heme and hemoglobin
A
- 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
14
Q
How many oxygen molecules does Hb transport and how is this involved in respiration?
A
- 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
15
Q
How is iron involved in the electron transport chain?
A
- 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
16
Q
Name 2 other important roles of iron?
A
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)
17
Q
How much iron do we lose per day and how does this occur?
A
- 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
18
Q
Based on how much we lose per day, how much iron do males and females need to absorb?
A
- Males need to absorb approx 1mg
- Females >1.5mg
- Late stage pregnancy 4-5mg to maintain blood volume in the fetus
19
Q
How much iron do infants need? Why do they need this amount?
A
- 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
20
Q
Why are weaning foods iron-fortified?
A
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
21
Q
What are EARs of iron based on?
A
- 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
22
Q
What are the DRIs for iron of people in different life stages?
A
23
Q
Why are RDAs higher than EAR?
A
- 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
24
Q
Why are the DRIs for non-vegetarians higher? How much higher?
A
- Vegetarians 1.8x higher
- Not eating meat so getting non-heme which has lower bioavailability
- Consuming inhibitors of iron as well
25
Why is the RDA for women taking oral contraceptives lower than non?
- 10.9mg vs 18mg because they do not have menstrual losses
26
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
27
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
28
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%)
29
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
30
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)**
31
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
32
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
33
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
34
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
35
Iron balance is primarily determined by ______________
Iron absorption
36
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
37
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
38
What will occur if someone has low iron?
- Use ferritin storage
- Ferroportin upregulated
- Increased proteins to get iron in as well
39
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)
40
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
41
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)
42
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
43
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)
44
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
45
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
46
What is an endogenous chelator?
Chelators in the body such as mucin lining GIT that forms a chelator with iron that actually improves absorption by protecting from strong chelators
47
What are iron chelators? What is their purpose?
- Chelators are molecules that bind metal ions
- Negatively charge so bind to any metal
- Small molecules (EDTA, AAs) or complex proteins (mucin, albumin, transferrin)
- Major purpose in iron homeostasis is to bind to, solubilize and make iron unavailable (i.e. oxygen reactions, toxicity, bacterial growth)
- Prevents precipitating in cells and becoming toxic
48
What chelators increase iron absorption?
- Ascorbate and citrate
- They are weak chelators meaning they help solubilize iron and transfer it from compounds to mucosal cells (some chelated molecules taken up via integrins?)
49
What chelators reduce iron absorption?
- Plant phytates and tannins
- Prevent uptake and absorption (can act as antioxidants if absorbed unbound i.e. phytic acid)
50
What is the function of chelation therapy?
- Chelators protect cells from iron-mediated toxicity (remove excess/neutralize free iron)
- Patients with anemia (low Hgb) with iron overload cannot give blood. Chelators help reduce amount of iron
- Chelators given to people with metal poisoning so excess is excreted in urine
- Iron-chelating agents (i.e. desferrioxamine, deferasirox) bind iron specifically (excreted in urine) whereas other iron chelators (i.e. EDTA) are broad-spectrum (bind with many different materials)
51
How can you maximize iron intake?
- Iron-enriched foods (i.e. grain products). Some may have low levels but consume several servings/day
- Co-nutrient feeding (increases bioavailability) such as meat factor protein e.g. ham and beans, vitamin C like bread or spinach + juice/tomato/strawberries
- Use iron cookware (in some beers due to Fe brewing vats)
- Supplements
52
What are the recommendations for 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 (already in ferrous form won't help but if in non-heme it will aid in reduction)
- Note: high Fe may cause GI distress, constipation (excess goes to colon and may have impacts)
53
What non-dietary factors may influence iron availability?
1) Turnover
- Hemoglobin, ferritin, and hemosiderin degradation yield plasma iron (recycling)
2) Excretion
- Mostly GI tract (blood, bile, desquamated mucosal cells)
- Skin (desquamation of surface cells)
- Urine
- Larger losses with hemorrhage, menses (Because blood is so concentrated with iron)
54
What are the early symptoms of hemochromatosis?
- chronic fatigue
- depression
- abdominal pain
- aching joints
- loss of sex drive (both sexes)
- Impotence (men)
- Menstrual irregularities or early menopause (women)
- Skin discoloration or bronzing
- Bacterial infections
55
What are the later symptoms of hemochromatosis?
- Type 2 diabetes
- Hypothyroidism
- Arrhythmia
- Heart failure
- Liver disorders (cirrhosis, liver cancer)
- Note: it is difficult to diagnose until extensive damage has occurred
56
What is hemochromatosis?
- iron toxicity and overload
- Most common genetic disorder affecting Canadians
- 1 in 9 people of mostly northern European descent are carriers of the most common type, 1 in 300 may have 2 copies of the gene that puts them at risk for iron overload
- Body absorbs 2-3x normal amount of iron, accumulated ~0.5 to 1g/yr
- Mutations in HFE gene causes inability to accurately sense iron stores therefore hepcidin not released (removal of inhibition)
- Iron builds up in vital organs, joints, and tissues (hemosiderosis)
- Increased transferrin saturation + increased ferritin = need more testing
- Transferrin becomes saturated → Increases highly reactive free iron in plasma → Increase free radical formation
57
Who is at risk of iron deficiency and why?
- Infants, especially premature with low body weight: low body stores + low iron in breast milk (lactoferrin)
- Children: high growth rate + low in diet (tend to consume lots of milk, not so much meat)
- Teens: rapid growth + poor diet + onset of menstruation
- Women (childbearing age): menstruation, pregnancy doubles demand
- Other risks: internal bleeding, kidney dialysis (blood loss + decreased EPO), GIT issues (decreased absorption), exclusionary diets (decreased iron in diet + increased foods that inhibit iron absorption)
58
Name the functional indicators of iron deficiency
- Impaired work capacity
- Impaired cognitive function
- Delayed psychomotor development (infants)
- Delayed immune function and intellectual development (children)
- Pregnancy complications (premature delivery, low birth weight, maternal anemia, increased perinatal infant mortality)
- Lead toxicity
59
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)
60
Why do most multivitamins for kids not contain iron?
They taste good so kids can eat too many which can lead to danger of iron overdose
61
What is the prevalence of iron deficiency?
- Canada's first comprehensive nutrition survey (70-72) found many segments of the population had dietary intake inadequacies, especially iron, calcium, vitamin D, and protein
- Worldwide 1-2 billion people affected by iron deficiency
- IDA most common nutritional deficiency in the world. Developing countries ~50% of children and pregnant women have iron deficiency (potentially related to hepcidin)
- Western countries: ~10% of toddlers, adolescent girls, women childbearing age affect by lack of dietary iron
62
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)
63
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
64
How many mg of iron in female and male bodies is normal?
28-32mg/kg
= 1540mg in females
= 2240mg in males
65
What is the turnover of senescent RBCs?
120 days
66
How many mg/d of iron do we need?
NEED ~20mg/d
- Diet 1-2mg, reutilization 18mg
67
What does transferrin do?
- Fe3+ form
- Transports iron in the circulation, supplies iron to cells
68
What does lactoferrin do?
- Fe3+ form
- Binds and removes iron from the circulation in infection
- In breast milk, bioavailable form
69
What does DMT1 stand for and what is its function?
- Divalent metal transporter 1
- Fe2+ form
- Transports Fe2+ across the apical membrane of enterocytes of the duodenum, and 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+
70
What is the function of ferroportin?
- Fe2+ form
- Exports Fe2+ across the basolateral membrane of duodenal enterocytes and exports Fe2+ from macrophages and hepatocytes
- acts with the multicopper oxidases ceruloplasmin and hephaestin to load apotransferrin with Fe3+
71
What is the function of ferritins?
- Fe3+
- Stores iron in the cytosol of many cells
- Synthesis is subject to regulation by iron regulatory protein/iron-responsive element
72
What is the function of hemosiderin?
- Fe3+ form
- Stores iron within lysosomes in conditions of iron loading
73
Name 6 iron transport/storage proteins
1. Transferrin
2. Lactoferrin
3. DMT1
4. Ferroportin
5. Ferritins
6. Hemosiderin
74
Name 2 Transferrin-Binding Proteins
1. TfR
2. Transferring receptor 2
75
What is TfR and what does it do?
- Transferrin receptor 1
- Principal protein for transferrin iron uptake
- Subject to regulation by iron regulatory proteins/iron-responsive elements
76
What is the function of transferrin receptor 2?
- Secondary protein for transferrin iron uptake
- Not subject to regulation by iron regulatory proteins/iron-responsive elements
- Involved in regulation of hepcidin transcription
77
Name 4 common proteins of iron recycling
1. Ceruloplasmin
2. Hephaestin
3. Duodenal cytochrome b (DcytB)
4. STEAP
78
What is the function of ceruloplasmin?
- Multicopper oxidase that oxidizes Fe2+ to Fe3+ before its incorporation into apotransferrin
- Circulating form of hephaestin
79
What is the function of Hephaestin?
- Multicopper oxidase that oxidizes Fe2+ to Fe3+ before its incorporation into apotransferrin
80
What is the function of DCytB?
- Duodenal cytochrome b
- Metalloreductase that reduces Fe3+ to Fe2+ before transport by DMT1 at the apical membrane of duodenal enterocytes
81
What is the function of STEAP?
- Six transmembrane epithelial antigen of the prostate
- Metalloreductase localized within endosomes that reduces Fe3+ to Fe2+ before transport by DMT1
- Unlike DCytB not specialized to one type of cell
82
What is erythropoeisis? When is it stimulated and what do you need for it?
- Production of erythrocytes (RBC)
- Highly regulated, multistep process that occurs in bone marrow
- Hypoxia detected in the kidney, releases erythropoietin, stimulates erythropoiesis
- Requires ~24mg Fe (~17mg incorporated into HgB) daily + constant supply of vitamin B12 and folic acid
83
When is heme formed?
Heme is formed when transferrin-bound iron is taken up by erythroblast and complexed in protoporphyrin in mitochondria
84
How is globin synthesis regulated?
- Iron regulates globin synthesis at transcriptional and translational levels, availability is regulated to ensure adequate supply for Hgb
85
What is the function of transferrin and where is it made?
-Major transport protein of iron in plasma
- apotransferrin synthesized in liver
- Presence of apotransferrin and ceruloplasmin in plasma ensures iron is immediately chelated, limiting toxicity/free radicals
- Each lobe of transferrin can transfer one iron so each transferrin molecule transfers 2 irons
- Higher affinity for Fe3+
- Each Tf molecule can carry 2 Fe3+ but usually only 30% saturated
86
How will transferrin concentrations change with iron deficiency?
- [Transferrin] may increase in iron deficiency, but is not a good indicator (Increases because it wants to be ready to transfer iron when it has come into the system)
- More likely to be affected by general malnutrition where it will decrease
87
What is serum transferrin (Tf) a mix of?
- Apotransferrin - protein with no bound cations (high binding affinity)
- Monoferric transferrin - protein bound to iron (Quite high affinity, not as high as apotransferrin)
- Diferric transferrin - protein bound to 2 irons (fully saturated at 30% with a 70% binding capacity)
88
What is TSAT? How do you calculate it?
Transferrin saturation = [serum iron] / TIBC x 100
- If normal [transferrin] in plasma = 2.5g/L or 30mmol/L and each Tf has 2 binding sites, then total potential binding = 60mmol/L (Total iron binding capacity (TIBC)
- If serum [iron] is 20mmol/L then Tf would be ~1/3 saturated and TSAT would be 30%
89
What does transferrin saturation <30% indicate vs >60%?
- Indicates depleted iron stores, <15% iron-deficient erythropoiesis. Would not be able to pick up free iron in blood and chelate for transport (would cause oxidative damage)
- >60% dangerous excess
90
How would transferrin change in early deficiency through continued iron depletion?
1. Early on, serum Tf increases but iron stores are not yet depleted. Serum iron concentrations would be normal = low to normal % saturation + high TIBC
2. When stores depleted, serum Tf still elevated but serum [Fe] low = low % saturation + very high TIBC
91
What is ferritin?
- Responsible for safe storage of iron = soluble, non-toxic, bioavailable form
92
What are the major sites of ferritin?
Reticulo-endothelial system (spleen - recycling RBC), parenchymal cells (liver, skeletal muscle), serum (normally reflects iron stores)
93
What do low, high, and normal ranges of ferritin demonstrate?
- Low = iron depletion (low serum iron + low ferritin means deficiency)
- High = iron overload OR inflammation (acute phase protein)
- Normal ranges: 18-270 (M) or 18-160 (F) ng/mL or mcg/L
94
What is apoferritin?
- Apoferritin is ferritin without iron (24 subunits: L&H)
95
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
96
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?
97
Research is currently exploring the use of hepcidin (or hepcidin agonist) to treat _____________________
Iron overload
98
Could a hepcidin antagonist be used to treat anemia of chronic disease/inflammation? Or iron deficiency?
- Hepcidin degrades ferroportin, the protein responsible for converting Fe2+ to Fe3+ for iron transfer to transferrin for cells in the body
- Inhibition of hepcidin would cause increased activity of ferroportin for cells to obtain iron
99
What are indicators of depleted iron stores, early functional iron deficiency, and iron deficiency anemia?
100
What are the stages of iron depletion and what occurs in each stage?
1. Iron storage depletion
- Low serum ferritin (interpret cautiously, if high then confirm w/ TSAT)
- No limitation in supply of iron to functional compartment
2. Mild iron deficiency without anemia
- Decreased transport iron due to iron-deficient erythropoiesis
- Reduced size of RBCs (mean corpuscular volume) due to decreased Hgb synthesis
3. Iron deficiency anemia
- Low blood [hemoglobin] = measurable deficit in functional department
- Note: Anemia may be due to other deficiencies (e.g. vit B12, it A, folate) or infections/inflammation (confirm cause with other measures)
101
What are iron-responsive elements (IREs)?
IREs are part of mRNA for many proteins and activation of a single protein has different effects on ferritin and transferrin receptor synthesis
102
When are IRE-binding proteins activated and what does their activation do?
- IRE-binding Proteins activated when cytosolic iron decreases, binds to IRE:
- Blocks formation of ferritin mRNA polysomes, restricts production of ferritin
- Stabilizes TfR mRNA (represses transcript degradation), increases TfR synthesis
103
How are IRE-BP impacted when iron is abundant?
- IRE-BP inactive and does not bind to IRE, ferritin synthesis proceeds unrestricted
104
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
105
What is soluble transferrin receptor (sTfR) and where is it found?
- Truncated form of tissue TfR; circulates as transferrin + receptor complex
- Highly expressed on all cells requiring iron but largest contributor to serum sTfR is erythoblasts (depends on marrow erythropoietin activity)
106
sTfR levels in blood indicate?
1. Erythropoietic activity: sTfR levels are decreased when erythropoiesis is decreased (less iron needed) and increased when erythropoiesis stimulated (more iron needed)
2. Iron status: sTfRs increase in iron deficiency anemia - body needs iron = Increased TfR expression
Note: [sTfR] may be normal if anemia is due to other factors such as inflammation, not iron deficiency (hepcidin production stimulated + increased ferritin)
107
What does the sTfR/ferritin ratio indicate?
Can reliably indicate iron availability over a wide range of iron stores
108
What is hepcin production reduced and induced by?
- Reduced by iron deficiency and erythropoiesis to increase iron supply
- Induced by iron loading + inflammation to prevent toxicity and limit availability to pathogens
109
What does hepcidin dysregulation result in?
Disorders of iron metabolism
110
What factors impact hepcidin synthesis?
- Bonn morphogenetic protein signaling (e.g. HJV, BMP6, SMAD)
- Inflammation (e.g. IL-6)
- Iron
- Erythropoeitic demand inhibits
- Hypoxia inhibits
111
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)
112
What is the function of transferrin receptor?
Trans-membrane glycoprotein important for cellular **uptake**; extracellular domain = binding site; cytoplasmic domain = intracellular trafficking/signal for endocytosis
113
How does the transferrin receptor work?
- Once iron load deposited in cell, apotransferrin not broken down but returns to circulation (rapid ~3-10 mins) along with soluble transferrin receptor (sTfR0
- the sTfR, which was part of extracellular domain, is proteolytically cleaved in the cell and released into plasma in proportion to the # of receptors → cells in need of iron have more receptors
- High amounts expresses need for iron. High amounts in cells that need iron because deficient or making RBC. Good indicator of iron need
114
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
